CN107735399A

CN107735399A - The big ring of chiral diaryl as the conditioning agent of protein kinase

Info

Publication number: CN107735399A
Application number: CN201680038613.1A
Authority: CN
Inventors: 景荣·J·崔; 李山; 李一山; E·W·罗杰斯; 翟大勇; 邓维; J·翁格
Original assignee: Tp Biopharmaceutical Co
Current assignee: Tp Biopharmaceutical Co; Turning Point Therapeutics Inc
Priority date: 2015-07-02
Filing date: 2016-06-30
Publication date: 2018-02-23
Anticipated expiration: 2036-06-30
Also published as: ES2864839T3; WO2017004342A1; KR102599788B1; JP2018519343A; JP6871903B2; AU2020217336A1; RU2018103907A3; KR20180023970A; AU2016287568B2; US20190284209A1; RU2732405C2; EP3317285A4; RU2018103907A; EP3317285A1; US10316044B2; CN107735399B; CA2989327A1; EP3317285B1; IL256377A; MX2017017097A

Abstract

The present invention relates to some chiral diaryl macrocyclic derivatives, the medical composition containing it, and the method using its treating cancer, pain, sacred disease, autoimmune disease and inflammation.

Description

The big ring of chiral diaryl as the conditioning agent of protein kinase

The cross reference of related application

Present application request on July in 2015 2 filed in U.S. provisional patent application cases the 62/188,043rd and The rights and interests of U.S. provisional patent application cases filed in 23 days June in 2016 the 62/353rd, 728, the whole of the application case are taken off Show that content is incorporated herein by reference.

Technical field

Cancer is treated the present invention relates to some chiral diaryl macrocyclic derivatives, the medical composition containing it and using it Disease, pain, sacred disease, the method for autoimmune disease and inflammation.

Background technology

Protein kinase is cell growth, propagation and the key regulator of survival.Heredity and epigenetic change are thin in cancer Built up in born of the same parents, malignant process is driven so as to cause the abnormal activation of Signal transduction pathway.Graceful peaceful G (Manning, G.) etc. People, science (Science) 2002,298,1912-1934.The pharmacology in these signal transduction paths suppresses that target on cancer treatment is presented The promising opportunity of getting involved of method.Suo Yesi C (Sawyers, C.), natural (Nature) 2004,432,294-297.

ALK and white blood cell EGFR-TK (LTK) belong to insulin receptor (IR) superfamily of receptor tyrosine kinase. ALK is mainly expressed in maincenter and peripheral neverous system, potential in the normal development of nervous system and function so as to show Effect.Pul Ford K (Pulford, K.) et al., cell and molecule life science (Cell Mol.Life Sci.) 2004, 61,2939.ALK for the first time be found in the form of fusion protein NPM (Nucleophosmin)-ALK, the fusion protein by from Move back the t (2 in shape large celllymphoma (ALCL) cell line；5)(p23；Q35) the fusion coding of chromosome translocation.Not This auspicious SW (Morris, S.W.) et al., science (Science) 1994,263,1281.Found in following kinds cancer ALK transpositions collocation thing unique more than 20 kinds, includes ALCL (the 60-90% incidences of disease), inflammatory myofibroblast tumour (IMT, 50-60%), non-small cell lung cancer (NSCLC, 3-7%), colorectal cancer (CRC, 0-2.4%), breast cancer (0-2.4%) And other carcinomas.Glan moral E (Grande, E.) et al., molecule treatment of cancer (Mol.Cancer Ther.) 2011,10, 569-579.ALK- fusion proteins are located in cytoplasm, and ALK fusion collocation thing leads in the dimerization of fusion protein or oligomerization Cross coiled-coil interaction come produce the composition of ALK kinase functions activation and work.Than Si Kefu D (Bischof, D.) et al., molecule and cell biology (Mol.Cell Biol.), 1997,17,2312-2325.Including echinoderm micro-pipe phase The EML4-ALK for closing (EML4) gene of albumen sample 4 and ALK gene has found in NSCLC for the first time, to be highly carcinogenic, and through exhibition Show and cause adenocarcinoma of lung in DNA murine turning to grow.Rope reaches M (Soda, M.) et al., natural (Nature) 2007,448,561- 566.There is ALK carcinogenicity point mutation in the familial and sporadic cases of spongioblastoma.Not this YP (Moss é, Y.P.) et al., natural (Nature) 2008,455,930-935.ALK is due to the important work in hematopoiesis, entity and mesenchymal neoplasm With and be cancer therapeutic intervene attractive molecular target.Glan moral (Grande), ibid.

The related receptor tyrosine kinase (Trk) of tropomyosin is the high-affinity receptor of neurenergen (NT), refreshing Through nerve growth factor (NGF) family that nutrient is protein.The member of Trk families is highly expressed in the cell of Origin of Innervation In.By its preferred neurenergen (NGF to TrkA, neurotrophic factor [BDNF] and NT4/5 to TrkB from brain, and NT3 to TrkC) activation Trk (TrkA, TrkB and TrkC) regulation development during neuron survival and differentiation.NT/Trk signals pass Guiding path serves as the endogenous system of protection neuron after biochemical lesion, transient ischemia or physical damnification.Di Le CJ (Thiele, C.J.) et al., Clinical Cancer Research (Clin.Cancer Res.) 2009,15,5962-5967.However, Trk is initially selected in the form of with the oncogene of the tropomyosin Gene Fusion in extracellular domain to be grown.By the dye in NTRK1 (TrkA) Activating mutations are in mamillary and medullary thyroid carcinoma and in recent years in non-small cell lung cancer caused by colour solid rearrangement or mutation In differentiate.Pi Luodi MA (Pierotti, M.A.) et al., cancer bulletin (Cancer Lett.) 2006,232,90- 98；Wa Shinaweiyi A (Vaishnavi, A.) et al., Natural medicine (Nat.Med.) 2013,19,1469-1472.Due to Trk plays an important role in sensation of pain and the conduction of growth of tumour cell and survival-signal, so the suppression of Trk receptor kinases Agent can provide the interests of the therapy as pain and cancer.

Jenas family kinase (Janus family of kinase) (JAK) includes JAK1, JAK2, JAK3 and TYK2, And conduct desired cytoplasmic tyrosine kinase for the physiological of cytohormone and growth factor.Elder brother Ta Si-Ka Dama A (Quintas-Cardama, A.) et al., comment on naturally：Drug discovery (Nat.Rev.Drug Discov.) 2011,10 (2), 127-40；Pesu, M. et al., immunology comment (Immunol.Rev.) 2008,223,132-142；Murray, P.J., it is immunized Learn magazine (J.Immunol.) 2007,178 (5), 2623-2329.The oligomerization that JAK is induced by part activates, under causing Trip is referred to as STAT (signal transducer and transcription activators) transcription signal conducting path activation.The STAT dimerization of phosphorylation and easily Expressed in core with the specific gene for driving participation propagation, cell carving to be died, breaking up, the gene is expressed as hematopoiesis, inflammation And immune response institute is required.In silent (Murray), ibid.

Mice gene knockouts study the main function for showing JAK-STAT signal transductions, are overlapped therebetween with some.JAK1 Pass is played in the signal transduction of various proinflammatory cytokine hormones (such as IL-1, IL-4, IL-6 and tumor necrosis factor α (TNF α)) Key acts on.Muller M (Muller, M.) et al., natural (Nature) 1993,366 (6451), 129-135.JAK2 is used for hematopoiesis Growth factor signal conduct, such as Epo, IL-3, IL-5, GM-CSF, TPO growth hormone and prolactin mediation Signal transduction.Neubauer H (Neubauer, H.) et al., cell (Cell) 1,998 93 (3), 397-409.JAK3 exempts from regulation Worked in epidemic disease reaction, and TYK2 is combined with transducer cell hormone (such as IL-12) signal with JAK2 or JAK3.Wild village T (Nosaka, T.) et al., science (Science) 1995,270 (5237), 800-802；The old Cole W of Wien (Vainchenker, W.) et al., cell and Developmental Biology seminar (Semin.Cell.Dev.Biol.) 2008,19 (4), 385-393。

The abnormal regulation in JAK/STAT paths has involved in a variety of human pathologies' property diseases, includes cancer (JAK2) and class Rheumatic arthritis (JAK1, JAK3).JAK2 gain-of-function mutation is found in MPN patient with high-frequency (JAK2V617F).Lay text RL (Levine, R.L.) et al., cancer cell (Cancer Cell) 2005,7 (4), 387-397； Carat sieve Vickers R (Kralovics, R.) et al., New England Journal of Medicine (N.Engl.J.Med.) 2005,253 (17),1779-1790；James C (James, C.) et al., natural (Nature) 2005,434 (7037), 1144-1148； Irving Baxter EJ (Baxter, E.J.) et al., lancet (Lancet) 2005,365 (9464), 1054-1061.JAK2's The mutation of JH2 vacations kinase domain produces composition kinase activity.Cell containing JAK2V617F mutation is obtained independent of cytohormone Growth ability and normally become tumour, so as to for develop JAK inhibitor provide strong reasonability as targeted therapies.

A variety of JAK inhibitor in clinical test are illustrated in the splenomegaly of myelofibrosis patient and the whole body that disease is related Quite big benefit in symptom, the first JAK2 inhibitor Lu Zuo comprising FDA approvals in 2011 replace Buddhist nun (ruxolitinib). Elder brother Ta Si-Ka Dama (Quintas-Cardama), ibid；Suo Boer MB (Sonbol, M.B.) et al., hematology therapy Be in progress (Ther.Adv.Hematol.) 2013,4 (1), 15-35；Drawing takes LM (LaFave, L.M.) et al., pharmacology trend (Trends Pharmacol.Sci.)2012,33(11),574-582.That collects in recent years faces with Lu Zuo for Buddhist nun's treatment is relevant Bed data instruction JAK inhibitor is applied to JAK2 wild types and JAK2 saltant type situations.Butterworth Tuo Saike S (Verstovsek, S.) et al., New England Journal of Medicine (N.Engl.J.Med.) 2012,366 (9), 799-807；Elder brother Ta Si-Ka Dama A (Quintas-Cardama, A.) et al., blood (Blood) 2010,115 (15), 3109-3117.JAK2 is relative to JAK1/3's The discovery of selective depressant is still unsolved challenge.In addition, JAK2/ signal transducers and the (JAK2/ of transcription activators 3 STAT3 overactivity) causes abnormal differentiation of dendritic cells, so that abnormal differentiation of dendritic cells and immune suppression in cancer Property bone marrow cell processed builds up (Nie Feiduowa Y (Nefedova, Y.) et al., cancer research (Cancer Res) 2005；65 (20):9525-35).In the aging tumour without Pten, inhibitive ability of immunity tumour micro-loop is established in the activation in Jak2/Stat3 paths Border, its facilitate tumour growth and chemoresistance (support rope A (Toso, A.) et al., cell report (Cell Reports) 2014, 9,75-89).Therefore, it can be to improve antitumor activity by adjusting antineoplastic immune that pharmacology, which suppresses JAK2/STAT3 paths, Important new therapeutic strategies.

ROS1 kinases is the unknown receptor tyrosine kinase of part.The normal function of mankind's ROS1 kinases is not yet complete Solution.However, the composition active fusion proteins in a variety of human cancers of ROS1 kinases generation genetic rearrangements generation have been reported, comprising Spongioblastoma, non-small cell lung cancer (NSCLC), cholangiocarcinoma, oophoroma, sdenocarcinoma of stomach, colorectal cancer, inflammatory flesh are into fibre Tieing up cytoma, angiosarcoma and epithelium shape nemendothelioma, (Davis KD (Davies, K.D.) et al., clinical cancer is ground Study carefully (Clin Cancer Res) 2013,19 (15):4040-4045).With gram Zhuo ROS1 fusions are targetted for Buddhist nun (crizotinib) Albumen shows promising clinical efficacy (Xiao AT in tumour is the positive NSCLC patient of ROS1 genetic abnormalities (Shaw, A.T.) et al., New England Journal of Medicine (N Engl J Med.) 2014,371 (21):1963-1971).Gram Zhuo is treated for Buddhist nun and observes that acquired resistance is mutated (A Wade MM (Awad, M.M.) et al., New England's medical science in patient Magazine (N Engl J Med.) 2013,368 (25):2396-2401).Second generation ROS1 inhibitor is developed to overcome gram Zhuo to replace Buddhist nun ROS1 drug resistances are very urgent.

EGFR-TK medicines of the Ke Zhuo for Buddhist nun (PF-02341066) for targeting MET/ALK/ROS1/RON, it has pin To TRK and AXL appropriateness activity.Cui JJ (Cui, J.J.) et al., pharmaceutical chemistry magazine (J.Med.Chem.) 2011,54, 6342-6363.Late period (the Locally Advanced or metastatic) NSCLC of its treatment of approved with abnormal expression ALK fusion gene Particular patient, the abnormal ALK fusion gene are tested (Vysis ALK are broken FISH probe set group) by Duplicate diagnostic and differentiated. Similar to Imatinib and other kinase inhibitor drugs, drug resistance is always produced after treating special time with gram Zhuo for Buddhist nun.Resistance Mechanism includes the abnormal activation of ALK gene amplification, Secondary cases ALK mutation and other kinases (including KIT and EGFR).Piece mountain R (Katayama, R.) et al., science translational medicine (Sci.Transl.Med.) 2012,4,120ra17.Based on treatment CML patient Imatinib-resistant second generation ABL inhibitor clinical success, there is second generation ALK inhibitor.This little medicine target Xiang Kezhuo replaces Buddhist nun intractable or the treatment of tolerance NSCLC patient, and it is respectively provided with to wild type with saltant type alk protein matter relatively has Effect suppresses.Auspicious Delhi C (Gridelli, C.) of lattice et al., treatment of cancer comment (Cancer Treat Rev.) 2014,40, 300-306。

Still need the micromolecular inhibitor with suitable pharmaceutical characteristic of these multiple proteins or EGFR-TK target. Have found that particular chiral diaryl macrocyclic compound has this favorable activity overview in the present case.

The content of the invention

In an aspect, the present invention relates to a kind of compound of formula I

Wherein

M is CR^4aOr N；

M¹For CR⁵Or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹For H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷Or- C(O)NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen atom in aryl is appointed Selection of land is independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkane Base)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl ,- N(C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkane Base) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆ Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkane Base) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH (C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O) NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH(C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆ Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

Each R²And R³It independently is H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Virtue Base ,-C (O) OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Aryl In each hydrogen atom optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkane Base) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC (O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkane Base)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkane Base ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkane Base) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkane Base ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N (C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；Or R² And R³C is optionally formed together with the carbon atom connected with it₅-C₇Cycloalkyl or 5 yuan are to 7 circle heterocycles alkyl；Or R²And R⁶With it The atom connected is optionally formed 5 yuan to 7 circle heterocycles alkyl together；

R⁴、R^4aAnd R⁵Respectively it independently is H, fluorine, chlorine, bromine, C₁-C₆Alkyl ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NHC₁-C₆Alkane Base ,-N (C₁-C₆Alkyl)₂Or-CF₃；

R⁶For H, C₁-C₆Alkyl or 3 yuan are to 7 circle heterocycles alkyl, wherein C₁-C₆It is each in alkyl or 3 yuan to 7 circle heterocycles alkyl Hydrogen atom is optionally independently through following substitution：Halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl )₂、C₃-C₆Cycloalkyl or it is monocyclic 5 yuan to 7 circle heterocycles alkyl；

Each R⁷And R⁸It independently is H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 3 yuan to 7 yuan Heterocyclylalkyl, C₆-C₁₀Aryl or heteroaryl；

Each R⁹It independently is H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 3 yuan to 7 circle heterocycles Alkyl, C₆-C₁₀Aryl or monocyclic or bicyclic heteroaryl；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 3 Member is to 7 circle heterocycles alkyl, C₆-C₁₀Each hydrogen atom in aryl or monocyclic or bicyclic heteroaryl optionally independently takes through following Generation：Deuterium, halogen, C₁-C₆Alkyl, C₁-C₆Alkylhalide group or-OR⁷；

Each Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶Or Z⁷It independently is N, NH or C (R¹⁰), wherein each R¹⁰Independently be H, deuterium, halogen, C₁-C₆Alkyl ,-OC₁-C₆Alkyl ,-OH ,-NH₂、-NH(C₁-C₆Alkyl) ,-NH (phenyl) ,-NH (heteroaryl) ,-CN or-CF₃,

N is 1 or 2；And

On condition that Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶Or Z⁷At least one of be N or NH；And on condition that at least one R¹、R²Or R³ It is not H；

Or its pharmaceutically acceptable salt.

In an aspect, the present invention relates to a kind of compound of Formulas I -1

Wherein

M is CR^4aOr N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹For C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen atom in aryl is optionally Independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl )₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkane Base) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆ Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkane Base) ,-NHS (O) NH₂、NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH (C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O) NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH(C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆ Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

R²And R³Respectively it independently is H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Virtue Base ,-C (O) OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Aryl In each hydrogen atom optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkane Base) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC (O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkane Base)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkane Base ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkane Base) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkane Base ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N (C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

Each Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶Or Z⁷It independently is N, NH or C (R¹⁰), wherein each R¹⁰Independently be H, deuterium, halogen, C₁-C₆Alkyl ,-OC₁-C₆Alkyl ,-OH ,-NH₂、-NH(C₁-C₆Alkyl) ,-NH (phenyl) ,-NH (heteroaryl) ,-CN or-CF₃, and

On condition that Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶Or Z⁷At least one of be N or NH；

Or its pharmaceutically acceptable salt.

In another aspect, the present invention relates to a kind of Formulas I a compounds

Wherein

M is CR^4aOr N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹For C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen atom in aryl is optionally Independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl )₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkane Base) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆ Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkane Base) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH (C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O) NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH(C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆ Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

Or its pharmaceutically acceptable salt.

In another aspect, the present invention relates to a kind of Formulas I b compounds

Wherein

M is CR^4aOr N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

N is 1 or 2；And

Or its pharmaceutically acceptable salt.

In another aspect, the present invention relates to a kind of Formulas I c compounds

Wherein

M is CR^4aOr N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Each Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶Or Z⁷It independently is N, NH or C (R¹⁰), wherein each R¹⁰Independently be H, deuterium, halogen, C₁-C₆Alkyl ,-O-C₁-C₆Alkyl ,-OH ,-NH₂、-NH(C₁-C₆Alkyl) ,-NH (phenyl) ,-NH (heteroaryl) ,-CN or-CF₃,

N is 1 or 2；And

Or its pharmaceutically acceptable salt.

In another aspect, the present invention relates to a kind of Formula II compound

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹And R²Respectively it independently is C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O)OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀It is each in aryl Hydrogen atom is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁- C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O)(C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkane Base ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N (C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、-C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

R⁴And R⁵Respectively it independently is H, fluorine, chlorine, bromine, C₁-C₆Alkyl ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl)₂Or-CF₃；

Each R⁷And R⁸It independently is H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 3 yuan to 7 yuan Heterocyclylalkyl, C₆-C₁₀Aryl or heteroaryl；And

Or its pharmaceutically acceptable salt.

In another aspect, the present invention relates to a kind of formula III compound

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹And R²Respectively it independently is C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O)OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀It is each in aryl Hydrogen atom is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁- C₆Alkyl, N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O)(C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkane Base ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N (C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

Or its pharmaceutically acceptable salt.

In another aspect, the present invention relates to a kind of formula IV compound

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹And R³Respectively it independently is C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O)OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀It is each in aryl Hydrogen atom is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁- C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O)(C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkane Base ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N (C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

Or its pharmaceutically acceptable salt.

In another aspect, the present invention relates to a kind of Formula V compound

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Or its pharmaceutically acceptable salt.

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Or its pharmaceutically acceptable salt.

In another aspect, the present invention relates to the compound selected from the group consisted of：

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R²And R³C is optionally formed together with the carbon atom connected with it₅-C₇Cycloalkyl or 5 yuan are to 7 circle heterocycles alkyl；

Or its pharmaceutically acceptable salt.

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R²And R⁶5 yuan are optionally formed together with the atom connected with it to 7 circle heterocycles alkyl；

Or its pharmaceutically acceptable salt.

In another aspect, the present invention relates to a kind of medical composition, it include Formulas I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII compound or its pharmaceutically acceptable salt and optional at least one Kind diluent, carrier or excipient.

In another aspect, the present invention is directed to a kind for the treatment of cancer, pain, sacred disease, autoimmune disease or inflammation Method, it include at least one Formulas I of the individual effective dose of this kind for the treatment of of administration needs, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII compound or its pharmaceutically acceptable salt.

In another aspect, the present invention for Formulas I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, The purposes of XI, XII or XIII compound or its pharmaceutically acceptable salt, it is used to prepare treating cancer, pain, neural disease The medicine of disease, autoimmune disease or inflammation.

In another aspect, the present invention for Formulas I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, The purposes of XI, XII or XIII compound or its pharmaceutically acceptable salt, its be used for treating cancer, pain, sacred disease, Autoimmune disease or inflammation.

In another aspect, the present invention for Formulas I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII compound or its pharmaceutically acceptable salt are used to prepare the medicine for treating this kind of disease and Medical Condition Purposes, and this kind of compound and salt is used to treat this kind of disease and the purposes of Medical Condition.

In another aspect, the present invention relates to one kind suppress protein or EGFR-TK (comprising MET, ALK, ROS1, One or more of AXL, TRK and JAK) method, its cell for including making including one or more of this kind of kinases with effectively At least one Formulas I of amount, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII chemical combination Thing or its pharmaceutically acceptable salt and/or contacted with least one medical composition of the invention, wherein the contact is in work In vitro, it is in vitro or in vivo carry out.

Other embodiments of the invention, feature and advantage will be by implementation below and by putting into practice the present invention and aobvious and easy See.The compounds of this invention can be as the embodiment description in any item listed below for bar.It is it will be appreciated that described herein any The degree that embodiment can not competed with each other with any other embodiment described herein with the embodiment is used in combination.

A kind of 1. compound of formula I

Wherein

M is CR^4aOr N；

M¹For CR⁵Or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

N is 1 or 2；And

Or its pharmaceutically acceptable salt.

A kind of compounds of Formulas I -1 of 1a.,

Wherein

M is CR^4aOr N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Or its pharmaceutically acceptable salt.

2. such as the compound of bar item 1 or 1a, it has Formulas I a

Wherein

M is CR^4aOr N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Or its pharmaceutically acceptable salt.

2a. such as bar item 1 or 1a compounds, it has Formulas I b

Wherein

M is CR^4aOr N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

N is 1 or 2；And

Or its pharmaceutically acceptable salt.

2b. such as bar item 1 or 1a compounds, it has Formulas I c

Wherein

M is CR^4aOr N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

N is 1 or 2；And

Or its pharmaceutically acceptable salt.

3. such as bar item 1,1a, 2,2a or 2b compound or its pharmaceutically acceptable salt, wherein Z¹、Z⁴And Z⁷For N and Z²、Z³、Z⁵And Z⁶For CH.

4. such as the compound or its pharmaceutically acceptable salt of any one of foregoing bar item, wherein X¹For N (R⁹)。

5. such as the compound or its pharmaceutically acceptable salt of any one of foregoing bar item, wherein R⁹For H.

6. such as the compound or its pharmaceutically acceptable salt of any one of foregoing bar item, wherein X²For O.

7. such as the compound or its pharmaceutically acceptable salt of any one of foregoing bar item, wherein R²For C₁-C₆Alkyl, C₂- C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkene Base, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen atom in aryl is optionally independently through following substitution：Deuterium, halogen Element ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁- C₆Alkyl) C (O) C₁-C₆Alkyl, NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkane Base) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O) OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、NHS(O)₂NH₂、-N (C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkane Base) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N (C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl )₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkane Base) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆ Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl, and R³For H.

8. such as the compound or its pharmaceutically acceptable salt of any one of bar item 1 to 6, wherein R²For H, and R³For C₁-C₆ Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkane Base, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen atom in aryl optionally independently takes through following Generation：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkane Base ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl, N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkane Base)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂ (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,- NHS(O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,- C(O)N(C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,- S(O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁- C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl.

9. such as the compound or its pharmaceutically acceptable salt of any one of bar item 1 to 6, wherein R²And R³For H.

10. such as the compound of any one of bar item 1 to 7, it has Formula II

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Or its pharmaceutically acceptable salt.

11. such as the compound of any one of bar item 1 to 7, it has formula III

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Or its pharmaceutically acceptable salt.

12. such as the compound of any one of bar item 1 to 6 or 8, it has formula IV

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹And R³Respectively it independently is C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O)OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀It is each in aryl Hydrogen atom is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁- C₆Alkyl, N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O)(C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkane Base ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N (C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

Or its pharmaceutically acceptable salt.

13. such as the compound of any one of bar item 1 to 6 or 8, it has Formula V

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Or its pharmaceutically acceptable salt.

14. such as the compound of any one of bar item 1 to 6 or 9, it has Formula IV

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Or its pharmaceutically acceptable salt.

The compound of 14a. such as any one of bar item 1,1a, 2 or 2a, it has the formula selected from the group consisted of：

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Or its pharmaceutically acceptable salt.

The compound of 14b. such as any one of bar item 1,1a, 2 or 2a, it has the formula selected from the group consisted of：

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Or its pharmaceutically acceptable salt.

15. such as the compound or its pharmaceutically acceptable salt of any one of foregoing bar item, wherein R⁵For-H.

16. such as the compound or its pharmaceutically acceptable salt of any one of foregoing bar item, wherein R⁴For-F.

17. such as the compound or its pharmaceutically acceptable salt of any one of bar item 1 to 7,10,11,15 or 16, wherein R² It is C in the presence of₁-C₆Alkyl and C₁-C₆Each hydrogen atom in alkyl is optionally independently through following substitution：Deuterium, halogen ,-OH ,- CN、-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O)C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl, N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkane Base ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkane Base) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆ Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,- NHS(O)N(C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆ Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆ Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁- C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O)N(C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl Or 3 yuan to 7 circle heterocycles alkyl.

18. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 7,10,11 or 15 to 17, wherein R²It is C in the presence of₁-C₆Alkyl, it is through selected from the substitution of one or more parts of the group consisted of：-F、-OH、-OC₁-C₆ Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) and-N (C₁-C₆Alkyl)₂。

19. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 7,10,11 or 15 to 18, wherein R²It is methyl in the presence of.

20. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 7,10,11 or 15 to 18, wherein R²It is ethyl in the presence of.

21. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 7,10,11 or 15 to 18, wherein R²It is hydroxymethyl in the presence of.

22. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 7,10,11 or 15 to 18, wherein R²It is methyl fluoride in the presence of.

23. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 7,10,11 or 15 to 18, wherein R²It is methoxy in the presence of.

24. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 7,10,11 or 15 to 18, wherein R²It is difluoromethyl in the presence of.

25. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 7,10,11 or 15 to 18, wherein R²It is trifluoromethyl in the presence of.

26. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 7,10,11 or 15 to 18, wherein R²It is C in the presence of₁-C₆Alkyl, its warp-NH₂、-NH(C₁-C₆Alkyl) or-N (C₁-C₆Alkyl)₂Substitution.

27. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 7,10,11 or 15 to 18, wherein R²It is methyl in the presence of, its warp-NH₂、-NH(C₁-C₆Alkyl) or-N (C₁-C₆Alkyl)₂Substitution.

28. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 7,10,11 or 15 to 18, wherein R²It is methyl in the presence of, its warp-N (CH₃)₂Substitution.

29. such as the compound or its pharmaceutically acceptable salt of any one of bar item 1 to 7,10,11,15 or 16, wherein R² In the presence of be-C (O) NR⁷R⁸。

30. such as the compound or its pharmaceutically acceptable salt of bar item 29, wherein R⁷And R⁸For H.

31. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 6,8,12,13,15 or 16, wherein R³In the presence of be C₁-C₆Alkyl and C₁-C₆Each hydrogen atom in alkyl is optionally independently through following substitution：Deuterium, halogen ,-OH ,- CN、-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O)C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl, N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkane Base ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkane Base) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆ Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,- NHS(O)N(C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆ Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆ Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁- C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O)N(C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl Or 3 yuan to 7 circle heterocycles alkyl.

32. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 6,8,12,13,15,16 or 31, Wherein R³In the presence of be C₁-C₆Alkyl, it is through selected from the substitution of one or more parts of the group consisted of：-F、-OH、- OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) and-N (C₁-C₆Alkyl)₂。

33. such as the compound of any one of bar item 1 to 6,8,12,13,15,16,31 or 32 or its is pharmaceutically acceptable Salt, wherein R³In the presence of be methyl.

34. such as the compound of any one of bar item 1 to 6,8,12,13,15,16,31 or 32 or its is pharmaceutically acceptable Salt, wherein R³In the presence of be ethyl.

35. such as the compound of any one of bar item 1 to 6,8,12,13,15,16,31 or 32 or its is pharmaceutically acceptable Salt, wherein R³In the presence of be hydroxymethyl.

36. such as the compound of any one of bar item 1 to 6,8,12,13,15,16,31 or 32 or its is pharmaceutically acceptable Salt, wherein R³It is methyl fluoride in the presence of.

37. such as the compound of any one of bar item 1 to 6,8,12,13,15,16,31 or 32 or its is pharmaceutically acceptable Salt, wherein R³It is methoxy in the presence of.

38. such as the compound of any one of bar item 1 to 6,8,12,13,15,16,31 or 32 or its is pharmaceutically acceptable Salt, wherein R³It is difluoromethyl in the presence of.

39. such as the compound of any one of bar item 1 to 6,8,12,13,15,16,31 or 32 or its is pharmaceutically acceptable Salt, wherein R³It is trifluoromethyl in the presence of.

40. such as the compound of any one of bar item 1 to 6,8,12,13,15,16,31 or 32 or its is pharmaceutically acceptable Salt, wherein R³It is C in the presence of₁-C₆Alkyl, its warp-NH₂、-NH(C₁-C₆Alkyl) or-N (C₁-C₆Alkyl)₂Substitution.

41. such as the compound of any one of bar item 1 to 6,8,12,13,15,16,31 or 32 or its is pharmaceutically acceptable Salt, wherein R³It is methyl in the presence of, its warp-NH₂、-NH(C₁-C₆Alkyl) or-N (C₁-C₆Alkyl)₂Substitution.

42. such as the compound of any one of bar item 1 to 6,8,12,13,15,16,31 or 32 or its is pharmaceutically acceptable Salt, wherein R³It is methyl in the presence of, its warp-N (CH₃)₂Substitution.

43. the compound or its pharmaceutically acceptable salt of such as any one of bar item 1 to 6,8,12,13,15 or 16, wherein R³It is-C (O) NR in the presence of⁷R⁸。

44. such as the compound or its pharmaceutically acceptable salt of bar item 43, wherein R⁷And R⁸For H.

45. such as the compound or its pharmaceutically acceptable salt of any one of foregoing bar item, wherein R¹It is C in the presence of₁- C₆Alkyl and C₁-C₆Each hydrogen atom in alkyl is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkane Base ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkane Base ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl, N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkane Base ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆ Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁- C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁- C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、- CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,- S(O)C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆ Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan to 7 yuan Heterocyclylalkyl.

46. such as the compound or its pharmaceutically acceptable salt of any one of foregoing bar item, wherein R¹It is C in the presence of₁- C₆Alkyl, it substitutes through one or more-F or-OH.

47. such as the compound or its pharmaceutically acceptable salt of any one of bar item 1 to 46, wherein R¹It is C in the presence of₁- C₆Alkyl.

48. such as the compound or its pharmaceutically acceptable salt of any one of bar item 1 to 46, wherein R¹It is first in the presence of Base.

49. such as the compound or its pharmaceutically acceptable salt of any one of bar item 1 to 46, wherein R¹It is second in the presence of Base.

50. such as the compound or its pharmaceutically acceptable salt of any one of bar item 1 to 46, wherein R¹It is 2- in the presence of Hydroxy-ethyl.

51. such as the compound or its pharmaceutically acceptable salt of any one of bar item 1 to 46, wherein R¹It is 2- in the presence of Fluoro- ethyl.

52. such as the compound or its pharmaceutically acceptable salt of any one of bar item 1 to 46, wherein R¹It is 2- in the presence of Hydroxyl -2- propyl group.

53. the compound or its pharmaceutically acceptable salt, wherein M such as any one of foregoing bar item are CR^4a。

54. the compound or its pharmaceutically acceptable salt, wherein M such as any one of foregoing bar item are CR^4a, and R^4aFor H。

55. such as the compound of bar item 1, it has the formula selected from the group consisted of：

Or its pharmaceutically acceptable salt.

56. such as the compound of bar item 1, it has the formula selected from the group consisted of：

Or its pharmaceutically acceptable salt.

57. such as the compound of bar item 1, it has the formula selected from the group consisted of：

Or its pharmaceutically acceptable salt.

58. such as the compound of bar item 1, it has the formula selected from the group consisted of：

Or its pharmaceutically acceptable salt.

59. such as the compound of bar item 1, it has the formula selected from the group consisted of：

Or its pharmaceutically acceptable salt.

60. such as the compound of bar item 1, it has the formula selected from the group consisted of：

Or its pharmaceutically acceptable salt.

61. a kind of medical composition, it includes the compound of any one of foregoing bar item or its pharmaceutically acceptable salt, And optionally at least a kind of diluent, carrier or excipient.

62. a kind for the treatment of cancer, pain, sacred disease, the method for autoimmune disease or inflammation, it includes administration needs At least one such as compound of any one of bar item 1 to 60 of the individual effective dose of this kind for the treatment of or its is pharmaceutically acceptable Salt.

63. a kind of such as compound of any one of bar item 1 to 60 or the purposes of its pharmaceutically acceptable salt, it is used to make For the medicine for the treatment of cancer, pain, sacred disease, autoimmune disease or inflammation.

64. a kind of such as compound of any one of bar item 1 to 60 or the purposes of its pharmaceutically acceptable salt, it is used to control Treat cancer, pain, sacred disease, autoimmune disease or inflammation.

A kind of 65. protein or tyrosine for suppressing to include one or more of MET, ALK, ROS1, AXL, TRK and JAK The method of kinases, it includes making at least one such as bar item 1 to 60 for the cell and effective dose for including one or more such kinases The compound of any one or its pharmaceutically acceptable salt and/or contacted with least one medical composition of the invention, wherein The contact in vitro, it is in vitro or in vivo carry out.

66. such as the compound of any one of bar item 1 to 60, it is used for the cancer for treating patient.

67. such as the compound of any one of bar item 1 to 60, it is used for the inflammation for treating patient.

Embodiment

Before further describing the invention, it should be understood that the present invention is not limited to the specific embodiment, therefore certainly variable Change.It should also be clear that term used herein merely for description specific embodiment purpose and be not intended to it is restricted because The scope of the present invention will be limited only by the appended claims.

Unless specified otherwise herein, otherwise all technologies used herein and scientific terminology have with it is of the art General technology person is generally understood identical implication.All patents, application case, disclosed application case mentioned by this paper and other Publication is incorporated herein in entirety by reference.If the definition illustrated in this part is with being herein incorporated by reference this The definition illustrated in patent, application case or other publication in text is opposite or is not inconsistent, then relative to by reference The definition being incorporated herein, based on the definition that is illustrated in this part.

Unless the context clearly, otherwise as used in herein and appended claims, singulative " one " and " described " include multiple indicants.It is further noted that claims can exclude any optional member through drafting Part.Therefore, the statement plan is served as advocates that key element uses the repulsion such as " only ", " only " and its similar terms with reference to narration Property term or use " negative sense " limit antecedent basis.

As used herein, term "comprising", " containing " and " comprising " are used with its opening, non-limiting sense.

To provide more succinct description, some quantitative expressions given herein limit without term " about ".No matter it will be appreciated that Whether term " about " is clearly used, and each amount given herein, which is intended to mean that, actually provides value, and it is also intended to provide value described in finger The approximation that will rationally be inferred based on one of ordinary skill in the art, comprising on it is described provide value be attributed to experiment And/or the equivalence value and approximation of measuring condition.Whenever with percents, to the rate of output, the yield is referred both to relative to can be The quality of the maximum amount of same entity of the entity obtained under specified chemical metered condition, wherein being produced for the entity Rate.Unless differently indicate, the concentration otherwise provided with percents refers to quality ratio.

Except as otherwise noted, otherwise the method for the embodiment of the present invention and technology are typically according to known in art and such as whole Cited and discuss various general and particularly the conventional method described in bibliography is carried out in the individual present invention.Referring to example Such as Loudon organic chemistry (Organic Chemistry) fourth edition, New York：Oxford University Press (Oxford University Press), 2002, the 360-361 pages, 1084-1085；Smith and the high of March, March organise Learn：Reaction, mechanism and structure (March's Advanced Organic Chemistry:Reactions,Mechanisms, And Structure), the 5th edition, U.S. Willie publishing house (Wiley-Interscience), 2001.

The chemical name of compound described herein typically using commercially available ACD/Name 2014 (ACD/Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer) are obtained.

It will be appreciated that can also be single for of the present invention special characteristic of the clarity described in the context of corresponding embodiment Combine and provide in embodiment.On the contrary, various spies of the invention described in the context of single embodiment for brevity Sign can also provide respectively or in the form of any suitable sub-portfolio.On all groups of the embodiment of chemical group represented by variable Close the journey for forgiving the compound (compound of i.e. separable, sign and test biology activity) for stable compound in this kind of combination Especially forgiven on degree by the present invention and it is open in this article, it is indivedual just as each combination and each combination and clearly disclose one As.In addition, all sub-portfolios of chemical group listed in describing the embodiment of this class variable also especially forgiven by the present invention and It is open in this article, it is indivedual just as each this kind of sub-portfolio of chemical group and each this kind of sub-portfolio and be clearly disclosed in this It is general in text.

Definition

As used herein, term " alkyl " includes carbon atom chain, and it is optionally side chain and contains 1 to 20 carbon atoms. It should be further appreciated that in certain embodiments, alkyl preferably has finite length, C is included₁-C₁₂、C₁-C₁₀、C₁-C₉、C₁-C₈、C₁- C₇、C₁-C₆And C₁-C₄.Illustratively, this kind of especially finite length alkyl, includes C₁-C₈、C₁-C₇、C₁-C₆And C₁-C₄And its class It is referred to alternatively as " low-carbon alkyl " like group.Illustrative alkyl is including (but not limited to) methyl, ethyl, n-propyl, isopropyl, positive fourth Base, isobutyl group, sec-butyl, the tert-butyl group, amyl group, 2- amyl groups, 3- amyl groups, neopentyl, hexyl, heptyl, octyl group and its similar group. Alkyl can be substituted or be unsubstituted.Typical substituents include cycloalkyl, aryl, heteroaryl, heterolipid ring, hydroxyl, alkoxy, virtue Epoxide, sulfydryl, alkyl sulfenyl, artyl sulfo, cyano group, halogen, carbonyl, oxo, (=O), sulfenyl carbonyl, O- carbamyls, N- Carbamyl, O- sulfenyls carbamyl, N- sulfenyls carbamyl, C- acylamino-s, N- acylamino-s, C- carboxyls, O- carboxyls, nitro and Amino, or as provided herein described in various embodiments.It will be appreciated that " alkyl " can be (such as provided above with other groups Group) combination, form functionalised alkyl.For example, the combination of " alkyl " and " carboxyl " can be described as " carboxyl as described herein Alkyl ".Other non-limiting examples include hydroxy alkyl, aminoalkyl and its similar group.

As used herein, term " alkenyl " includes carbon atom chain, and it is optionally side chain, and contains 2 to 20 carbon atoms, And include at least one carbon-to-carbon double bond (i.e. C=C).It will be appreciated that in certain embodiments, alkenyl preferably has finite length, bag Containing C₂-C₁₂、C₂-C₉、C₂-C₈、C₂-C₇、C₂-C₆And C₂-C₄.Illustratively, this kind of especially finite length alkenyl, includes C₂-C₈、 C₂-C₇、C₂-C₆And C₂-C₄It can be described as low-carbon alkenyl.Alkenyl can be unsubstituted, or as described in for alkyl or as provided herein It is substituted described in various embodiments.Illustrative alkenyl is including (but not limited to) vinyl, 1- acrylic, 2- acrylic, 1-, 2- Or 3- cyclobutenyls and its similar group.

As used herein, term " alkynyl " includes carbon atom chain, and it is optionally side chain, and contains 2 to 20 carbon atoms, And include at least one carbon-to-carbon triple bond (i.e. C ≡ C).It will be appreciated that in certain embodiments, alkynyl preferably respectively has finite length, Include C₂-C₁₂、C₂-C₉、C₂-C₈、C₂-C₇、C₂-C₆And C₂-C₄.Illustratively, this kind of especially finite length alkynyl, includes C₂-C₈、 C₂-C₇、C₂-C₆And C₂-C₄, can be described as low-carbon alkynyl.Alkynyl can be unsubstituted, or as described in for alkyl or as provided herein It is substituted described in various embodiments.Illustrative alkynyl is including (but not limited to) acetenyl, 1- propinyls, 2-propynyl, 1-, 2- Or 3- butynyls and its similar group.

As used herein, term " aryl " refers to the full carbon list of 6 to 12 carbon atoms of the pi-electron system with total conjugated Ring or condensed ring polycyclic moiety.It will be appreciated that in certain embodiments, aryl preferably has limited size, such as C₆-C₁₀Aryl.Explanation Property aryl is including (but not limited to) phenyl, naphthyl and anthryl.Aryl can be unsubstituted, or as described in for alkyl or as carried herein It is substituted described in the various embodiments supplied.

As used herein, it is monocyclic to refer to 3 yuan to 15 yuan full carbon for term " cycloalkyl ", thick comprising complete 5 yuan/6 yuan or 6 yuan/6 yuan of carbon Close bicyclic, or (it is adjacent that " thick " loop system means that each ring in system is shared with each another ring in the system to polycyclic fused ring Carbon atom to) group, wherein one or more rings can contain one or more double bonds, but cycloalkyl is free of the pi-electron system of total conjugated System.It will be appreciated that in certain embodiments, cycloalkyl preferably has limited size, such as C₃-C₁₃、C₃-C₉、C₃-C₆And C₄-C₆.Cycloalkanes Base can be unsubstituted, or be substituted as described in for alkyl or as provided herein described in various embodiments.Illustrative cycloalkanes Base is including (but not limited to) cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclopentadienyl group, cyclohexyl, cyclohexenyl group, cycloheptyl Base, adamantyl, norborneol alkyl, norbornene, 9H- fluorenes -9- bases and its similar group.Illustrated cycloalkyl Illustrative example includes the entity of following appropriate bond portion-form：

As used herein, there is the monocyclic or condensed ring group of 3 to 12 annular atoms in term " Heterocyclylalkyl " finger ring, wherein At least one annular atom is hetero atom (such as nitrogen, oxygen or sulphur), and remaining annular atom is carbon atom.Heterocyclylalkyl optionally contains 1st, 2,3 or 4 hetero atoms.Heterocyclylalkyl can also have one or more double bonds, comprising the double bond (such as C=N or N=N) with nitrogen, But the pi-electron system without total conjugated.It will be appreciated that in certain embodiments, Heterocyclylalkyl preferably has limited size, such as 3 Member is to 7 circle heterocycles alkyl, 5 yuan to 7 circle heterocycles alkyl and its similar group.Heterocyclylalkyl can be unsubstituted, or such as alkyl It is substituted described in various embodiments described or as provided herein.Illustrative Heterocyclylalkyl is including (but not limited to) oxirane Base, thiophene alkaryl, azetidinyl, oxetanyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl, 1,4- dioxanes base, morpholinyl, 1,4- dithiane base, piperazinyl, oxepane alkyl, 3,4- dihydro -2H- pyrans Base, 5,6- dihydro -2H- pyranoses, 2H- pyranoses, 1,2,3,4- tetrahydro pyridyls and its similar group.Illustrated is miscellaneous The illustrative example of cycloalkyl includes the entity of following appropriate bond portion-form：

As used herein, term " heteroaryl " refers to the monocyclic or condensed ring group with 5 to 12 annular atoms, the annular atom Containing one, two, three or four ring hetero atom for being selected from nitrogen, oxygen and sulphur, remaining annular atom is carbon atom, and has total conjugated Pi-electron system.It will be appreciated that in certain embodiments, heteroaryl preferably has a limited size, for example, 3 yuan to 7 unit's heteroaryls, 5 yuan To 7 unit's heteroaryls and its similar group.Heteroaryl can be unsubstituted, or as described in for alkyl or as provided herein various realities Apply and be substituted described in example.Illustrative heteroaryl is including (but not limited to) pyrrole radicals, furyl, thienyl, imidazole radicals, oxazole Base, thiazolyl, pyrazolyl, pyridine radicals, pyrimidine radicals, quinolyl, isoquinolyl, purine radicals, tetrazole radical, triazine radical, pyrazinyl, four Piperazine base, quinazolyl, quinoline quinoline base, thienyl, isoxazolyl, isothiazolyl, oxadiazoles base, thiadiazolyl group, triazolyl, benzo Imidazole radicals, benzoxazolyl, benzothiazolyl, benzo isoxazolyl, benzisothia oxazolyl and carbazole acyl group and its similar group. The illustrative example of illustrated heteroaryl includes the entity of following appropriate bond portion-form：

As used herein, " hydroxyl (hydroxy/hydroxyl) " refers to-OH groups.

As used herein, " alkoxy " refers to-O- (alkyl) or-O- (cycloalkyl being unsubstituted) group.Representative example Including (but not limited to) methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy And its similar group.

As used herein, " aryloxy group " refers to-O- aryl or-O- heteroaryls.Representative example is including (but not limited to) benzene oxygen Base, pyridine epoxide, furans epoxide, thiophene oxy, 2-pyrimidinyl oxy, pyrazine epoxide and its similar group.

As used herein, " sulfydryl " refers to-SH groups.

As used herein, " alkyl sulfenyl " refers to-S- (alkyl) or-S- (cycloalkyl being unsubstituted) group.It is representative real Example is including (but not limited to) methylsulfany, ethylsulfanyl, propyl group sulfenyl, butyl sulfenyl, cyclopropylsulfanyl, cyclobutyl sulfenyl, ring Pentylthio, cyclohexylthio and its similar group.

As used herein, " artyl sulfo " refers to-S- aryl or-S- heteroaryls.Representative example is including (but not limited to) benzene Base sulfenyl, pyridinylthio, furyl sulfenyl, thienyl sulfenyl, pyrimidine-based sulfur-base and its similar group.

As used herein, " halogen " or " halogen " refers to fluorine, chlorine, bromine or iodine.

As used herein, " cyano group " refers to-CN groups.

Term " oxo " represents ketonic oxygen.For example, the cyclopenta substituted through oxo is cyclopentanone.

As used herein, " key " refers to covalent bond.

Term " being substituted " means that specified group or part have one or more substituents.Term " being unsubstituted " is meaned Specified group and do not have substituent.When term " being substituted " is used for description scheme system, substitution means to appear in system On any valence mumber allow position.In certain embodiments, " being substituted " means that specified group or part have one, two Or three substituents.In other embodiments, " being substituted " means that specified group or part have one or two substituents. In other embodiments, " being substituted " means that specified group or part have a substituent.

As used herein, " it is optionally present " or " optionally " means the event then described or situation may but may not Occur, and situation of the description comprising event or situation generation and its nonevent situation.For example, " wherein C₁-C₆Alkane Base, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 3 yuan to 7 circle heterocycles alkyl, C₆-C₁₀Aryl or monocyclic or bicyclic heteroaryl In each hydrogen atom optionally independently through C₁-C₆Alkyl substitutes " mean that alkyl may but may not be by replacing the hydrogen of each alkyl Atom and be present in C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 3 yuan to 7 circle heterocycles alkyl, C₆-C₁₀Aryl Or on any one of monocyclic or bicyclic heteroaryl, and the description includes C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆ Cycloalkyl, 3 yuan to 7 circle heterocycles alkyl, C₆-C₁₀Aryl or monocyclic or bicyclic heteroaryl are through alkyl-substituted situation and C₁-C₆Alkane Base, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 3 yuan to 7 circle heterocycles alkyl, C₆-C₁₀Aryl or monocyclic or bicyclic heteroaryl Without alkyl-substituted situation.

As used herein, " independently " mean that the event that then describes or situation should be relative to other similar incidents or rings Border is understood with regard to its own.For example, in the case where there, wherein counting equivalent hydrogen-based optionally through another described in situation One group substitutes, and use " optionally independently " means that each situation of hydrogen atom on group can substitute through another group, wherein The group for replacing each hydrogen atom may be the same or different.Or for example, if there is multiple groups, it may be selected from possibility Group, then use " independently " means that each group can be selected from possibility group independently of any other group, and the situation In selected group may be the same or different.

As used herein, term " pharmaceutically acceptable salt " refers to relative ion available for those salt in medicine.Typically Referring to SM uncles outstanding (S.M.Berge) et al., " pharmaceutical salts (Pharmaceutical Salts) ", Journal of Pharmaceutical Sciences (J.Pharm.Sci.),1977,66,1-19.It is pharmaceutically acceptable preferably salt for pharmacologically effectively and be applied to and individual Tissue contact and without improper toxicity, stimulation or the salt of allergic reaction.Compound as described herein can have base acid enough Group, the enough group of alkalescence, two kinds of functional group or more than a kind of all types of functional groups, thus with it is a variety of inorganic or have Machine alkali and inorganic and organic acid reaction form pharmaceutically acceptable salt.This kind of salt includes：

(1) acid-addition salts, it can pass through the free alkali of parent compound and inorganic acid (such as hydrochloric acid, hydrobromic acid, nitric acid, phosphorus Acid, sulfuric acid and cross chloric acid and its similar acid) or with organic acid (such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, Loprazolam, ethane sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like) it is anti- It should obtain；Or

(2) acid proton present in the parent compound through metal ion (such as alkali metal ion, alkaline-earth metal ions or Aluminium ion) displacement；Or (such as monoethanolamine, diethanol amine, triethanolamine, trishydroxymethylaminomethane, N- methyl are also with organic base Former aminoglucose and the like) coordination when the salt that is formed.

Pharmaceutically acceptable salt is well known to those skilled in the art, and any this kind of pharmaceutically acceptable salt can be tied Embodiment as described herein is closed to be covered.The example of pharmaceutically acceptable salt includes sulfate, pyrosulfate, hydrogen sulfate Salt, sulphite, bisulfites, phosphate, hydrophosphate, dihydric phosphate, metaphosphate, pyrophosphate, chloride, bromine Compound, iodide, acetate, propionate, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthic acid Salt, propiolate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleic two Hydrochlorate, butine -1,4- diacid salts, hexin -1,6- diacid salts, benzoate, chloro benzoate, methyl benzoic acid salt, dinitro Benzoate, hydroxy benzoate, methoxy benzoic acid salt, phthalate, sulfonate, metilsulfate, propyl sulfonic acid Salt, benzene sulfonate, xylenesulfonate, naphthalene -1- sulfonate, naphthalene-2-sulfonic acid salt, phenylacetate, phenpropionate, benzenebutanoic acid salt, Citrate, lactate, γ-hydroxybutyric acid salt, glycollate, tartrate and mandelate.It is pharmaceutically acceptable other suitable The list for closing salt sees Lei Mingdengshi pharmacy pandect (Remington's Pharmaceutical Sciences), the 17th edition, horse Gram publishing company (Mack Publishing Company), Easton, Pennsylvania, in 1985.

For the Formulas I containing basic nitrogen, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII Or XIII compound, pharmaceutically acceptable salt can be prepared by available any appropriate methodology in art, such as with Inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, amine sulfonic acid, nitric acid, boric acid, phosphoric acid and its similar acid) or with organic acid (such as second Acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxy-maleic acid, isethionic acid, fourth Diacid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic, salicylic acid, oleic acid, palmitic acid, laurate, pyrans Saccharic acid (such as glucuronic acid or galacturonic acid), 'alpha '-hydroxy acids (such as tussol, citric acid or tartaric acid), amino acid (example Such as aspartic acid or bran propylhomoserin), aromatic acid (such as benzoic acid, Aspirin, naphthoic acid or cinnamic acid), sulfonic acid (such as lauryl sulfonic acid, p-methyl benzenesulfonic acid, Loprazolam or ethane sulfonic acid) or acid (such as given herein as example Acid) any compatible blend) and according to general technology level in the technology be considered as equivalent or acceptable substitute appoint What its acid and its mixture processing free alkali.

The present invention also on Formulas I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or The pharmaceutically acceptable prodrug of XIII compound and the treatment method using this kind of pharmaceutically acceptable prodrug.Term " prodrug " means the precursor of appointed compound, and it is in vivo (such as molten by chemically or physiologically method after administration individual Agent decomposition or enzymatic lysis) or under physiological conditions produce compound (such as prodrug is converted into formula when reaching physiology pH I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII compound)." it can pharmaceutically connect The prodrug received " can tolerate for nontoxic, biology and biologically be applied to the prodrug to individual administration in other side.For selecting The illustrative program description of suitable prodrug derivant is selected and prepared in such as " prodrug design (Design of Prodrugs) ", is compiled Volume H Bond's dagger-axe morals (H.Bundgaard), Ai Siweier (Elsevier), in 1985.

The present invention also on Formulas I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or The purposes of the pharmaceutical active metabolin and this metabolite of XIII compound in the methods of the invention." pharmaceutical active metabolin " Mean Formulas I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII compound or its The pharmacological activity product that salt is metabolized in vivo.Or can known in the usable art of the prodrug and active metabolite of compound Routine techniques determines.See, for example, Bel Tuoli Buddhist nun (Bertolini) et al., pharmaceutical chemistry magazine (J.Med.Chem.) 1997,40,2011-2016；Single (Shan) et al., Journal of Pharmaceutical Sciences (J.Pharm.Sci.) 1997,86 (7), 765-767； Ba Gexiao (Bagshawe), Drug development and research (Drug Dev.Res.) 1995,34,220-230；Baudot that (Bodor), Advanced drug delivery comments on (Adv.Drug Res.) 1984,13,255-331；Bond's dagger-axe moral (Bundgaard), prodrug design (Design of Prodrugs) (Ai Siweier publishing houses, 1985)；And Larsen (Larsen), prodrug design and application (Design and Application of Prodrugs), drug design and exploitation (Drug Design and Development) (Krogsgaard-Larsen et al. is compiled, Wood academic press, Kazakhstan, 1991).

Any formula depicted herein is intended to represent the compound and some changes or form of the structural formula.Citing comes Say, formula used herein intend comprising racemic form or one or more enantiomerisms, diastereo-isomerism or geometric isomer or Its mixture.In addition, any formula used herein is intended to be also refer to the hydrate, solvate or polymorph of this kind of compound Or its mixture.For example, it should be understood that by containing symbolStructural formula describe compound include symbolTwo kinds of stereoisomers of the carbon atom connected, especiallyImplication cover keyWithFor example, in some one exemplary embodiments, specific compound provided in this article can be described by following formula：

The formula is interpreted as covering the compound at relevant carbon atom with two kinds of three-dimensional chemical configurations, especially at this In individual example

Any formula given in this paper is also intended to represent the un-marked form of compound and through isotope marks Form.Compound through isotope marks has the structure described by chemical formula given herein, difference be one or Multiple atoms are by the atomic substitutions with selected atom quality or mass number.The reality for the isotope that may be incorporated into the compounds of this invention Example includes the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, respectively for example²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl and¹²⁵I.This kind of compound through isotope marks is applied to：Metabolism research (preferably uses¹⁴C)；Reaction Dynamics research is (using for example²H or³H)；Detection or imaging technique [such as positron emission tomography (PET) or monochromatic light Son transmitting computerized tomography (SPECT)], comprising medicine or by matter tissue distribution assays；Or the radiation suitable for patient Property treatment.In addition, with such as deuterium (i.e.²H higher isotope substitution) can obtain some to be controlled as caused by more greater metabolic stability Treatment advantage, such as increased vivo half-life or the volume requirements of reduction.The compound through isotope marks of the present invention and Its prodrug typically can be by carrying out in flow or examples described below and the program disclosed in preparing, by using can be easy It is prepared by the reagent of the substitution nonisotopic labels of the reagent through isotope marks obtained.

When allowing more than a kind of connection possibility, mentioned by this paper it is any it is disubstituted plan forgive it is various it is this kind of can Can property.For example, disubstituted-A-B-, wherein A ≠ B are referred to, refer to this kind of disubstituted there is A to be connected to the herein Be connected to second once substitution member and B and be substituted member, and its also refer to it is this kind of it is disubstituted have A be connected to the second member and B is connected to first and is substituted member.

Representative embodiment

In certain embodiments, compound described herein includes the part of following formula

Wherein Z¹-Z⁷It is defined as described herein.In other embodiments, compound described herein includes the portion of following formula Point

Wherein Z¹-Z⁷Definition in addition as described herein.In other embodiments, compound described herein includes the portion of following formula Point

In other embodiments, compound described herein includes the part of following formula：

In other embodiments, chemical combination described herein Thing includes the part of following formula：

In certain embodiments, Z¹、Z⁴And Z⁷For N, and Z²、Z³、Z⁵And Z⁶For C (R¹⁰).In certain embodiments, Z¹、Z⁴And Z⁷For N, and Z²、Z³、Z⁵And Z⁶For C (R¹⁰), wherein each R¹⁰For H.In certain embodiments, Z¹And Z³For N, Z⁷For NH and Z²、Z⁴、 Z⁵And Z⁶For C (R¹⁰).In certain embodiments, Z¹And Z³For N, Z⁷For NH and Z²、Z⁴、Z⁵And Z⁶For C (R¹⁰), wherein each R¹⁰For H. In certain embodiments, Z¹、Z³And Z⁶For N, Z⁷For NH, and Z²、Z⁴And Z⁵For C (R¹⁰).In certain embodiments, Z¹、Z³And Z⁶For N, Z⁷For NH and Z²、Z⁴And Z⁵For C (R¹⁰), wherein each R¹⁰For H.In certain embodiments, Z³For N, Z⁷For NH and Z¹、Z²、Z⁴、Z⁵ And Z⁶For C (R¹⁰).In certain embodiments, Z³For N, Z⁷For NH and Z¹、Z²、Z⁴、Z⁵And Z⁶For C (R¹⁰), wherein each R¹⁰For H. In some embodiments, Z³And Z⁶For N, Z⁷For NH and Z¹、Z²、Z⁴And Z⁵For C (R¹⁰).In certain embodiments, Z³And Z⁶For N, Z⁷For NH and Z¹、Z²、Z⁴And Z⁵For C (R¹⁰), wherein each R¹⁰For H.In certain embodiments, Z²、Z⁴And Z⁷For N, and Z¹、Z³、Z⁵And Z⁶For C(R¹⁰).In certain embodiments, Z²、Z⁴And Z⁷For N and Z¹、Z³、Z⁵And Z⁶For C (R¹⁰), wherein each R¹⁰For H.In some implementations In example, Z¹、Z⁵And Z⁷For N and Z²、Z³、Z⁴And Z⁶For C (R¹⁰).In certain embodiments, Z¹、Z⁵And Z⁷For N and Z²、Z³、Z⁴And Z⁶ For C (R¹⁰), wherein each R¹⁰For H.In certain embodiments, Z¹、Z²、Z⁴And Z⁷For N and Z³、Z⁵And Z⁶For C (R¹⁰).In some realities Apply in example, Z¹、Z²、Z⁴And Z⁷For N and Z³、Z⁵And Z⁶For C (R¹⁰), wherein each R¹⁰For H.In certain embodiments, Z¹、Z²、Z⁵And Z⁷ For N and Z³、Z⁴And Z⁶For C (R¹⁰).In certain embodiments, Z¹、Z²、Z⁵And Z⁷For N and Z³、Z⁴And Z⁶For C (R¹⁰), wherein each R¹⁰ For H.In certain embodiments, Z³、Z⁵And Z⁶For N and Z¹、Z²、Z⁴And Z⁷For C (R¹⁰).In certain embodiments, Z³、Z⁵And Z⁶For N And Z¹、Z²、Z⁴And Z⁷For C (R¹⁰), wherein each R¹⁰For H.In certain embodiments, Z¹、Z⁵、Z⁶And Z⁷For N and Z²、Z³And Z⁴For C (R¹⁰).In certain embodiments, Z¹、Z⁵、Z⁶And Z⁷For N and Z²、Z³And Z⁴For C (R¹⁰), wherein each R¹⁰For H.In some embodiments In, Z¹、Z²And Z⁴For N and Z³、Z⁵、Z⁶And Z⁷For C (R¹⁰).In certain embodiments, Z¹、Z²And Z⁴For N and Z³、Z⁵、Z⁶And Z⁷For C (R¹⁰), wherein each R¹⁰For H.In certain embodiments, Z¹、Z³And Z⁴For N and Z²、Z⁵、Z⁶And Z⁷For C (R¹⁰).In some embodiments In, Z¹、Z³And Z⁴For N and Z²、Z⁵、Z⁶And Z⁷For C (R¹⁰), wherein each R¹⁰For H.In certain embodiments, Z³And Z⁴For N and Z¹、 Z²、Z⁵、Z⁶And Z⁷For C (R¹⁰).In certain embodiments, Z³And Z⁴For N and Z¹、Z²、Z⁵、Z⁶And Z⁷For C (R¹⁰), wherein each R¹⁰For H.In certain embodiments, Z²、Z⁵And Z⁷For N and Z¹、Z³、Z⁴And Z⁶For C (R¹⁰).In certain embodiments, Z²、Z⁵And Z⁷For N and Z¹、Z³、Z⁴And Z⁶For C (R¹⁰), wherein each R¹⁰For H.In certain embodiments, Z³And Z⁵For N and Z¹、Z²、Z⁴、Z⁶And Z⁷For C (R¹⁰).In certain embodiments, Z³And Z⁵For N and Z¹、Z²、Z⁴、Z⁶And Z⁷For C (R¹⁰), wherein each R¹⁰For H.In some embodiments In, Z²、Z⁵、Z⁶And Z⁷For N and Z¹、Z³And Z⁴For C (R¹⁰).In certain embodiments, Z²、Z⁵、Z⁶And Z⁷For N and Z¹、Z³And Z⁴For C (R¹⁰), wherein each R¹⁰For H.

In certain embodiments, X¹For-N (R⁹)-.In certain embodiments, X²For-O-.In certain embodiments, X¹For- N(R⁹)-, and X²For-O-.In certain embodiments, M is CH or N.In certain embodiments, M N.In certain embodiments, M For CH.In certain embodiments, M¹For CH or N.In certain embodiments, M¹For N.In certain embodiments, M¹For CH.

In certain embodiments, R¹For C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,- C(O)OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀In aryl Each hydrogen atom is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkane Base) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC (O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkane Base)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkane Base ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkane Base) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkane Base ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N (C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl.

In certain embodiments, R¹For C₁-C₆Alkyl, wherein each hydrogen atom is optionally independently through following substitution：Deuterium, halogen Element ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁- C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆ Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O) OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、- N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkane Base) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N (C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl )₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkane Base) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆ Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl.

In certain embodiments, R¹For methyl, ethyl, isopropyl, 2- hydroxyl -2- propyl group, 2- hydroxyethyls or 2- fluorine second Base.In certain embodiments, R¹For methyl.In certain embodiments, R¹For ethyl.In certain embodiments, R¹For isopropyl. In certain embodiments, R¹For 2- hydroxyl -2- propyl group.In certain embodiments, R¹For 2- hydroxyethyls.In certain embodiments, R¹For 2- fluoro ethyls.In certain embodiments, R¹For D₃C-.In certain embodiments, R¹For-C (O) NH₂、-C(O)NH(C₁-C₆ Alkyl) or-C (O) N (C₁-C₆Alkyl).In certain embodiments, R¹For-C (O) NHCH₃.In certain embodiments, R¹For-C (O) N(CH₃)₂.In certain embodiments, R¹For cyano methyl.

In certain embodiments, R²For C₁-C₆Alkyl or-C (O) NR⁷R⁸, wherein C₁-C₆Each hydrogen atom in alkyl is optional Ground is independently through selected from the substitution of one or more parts of the group consisted of：-F、-OH、-OC₁-C₆Alkyl ,-NH₂、-NH (C₁-C₆Alkyl) and-N (C₁-C₆Alkyl)₂.In certain embodiments, R²For C₁-C₆Alkyl or-C (O) NR⁷R⁸, wherein C₁-C₆Alkane Each hydrogen atom in base is optionally independently through selected from the substitution of one or more parts of the group consisted of：-F、-OH、- OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) and-N (C₁-C₆Alkyl)₂, and R³For H.

In certain embodiments, R³For C₁-C₆Alkyl or-C (O) NR⁷R⁸, wherein C₁-C₆Each hydrogen atom in alkyl is optional Ground is independently through selected from the substitution of one or more parts of the group consisted of：-F、-OH、-OC₁-C₆Alkyl ,-NH₂、-NH (C₁-C₆Alkyl) and-N (C₁-C₆Alkyl)₂.In certain embodiments, R³For C₁-C₆Alkyl or-C (O) NR⁷R⁸, wherein C₁-C₆Alkane Each hydrogen atom in base is optionally independently through selected from the substitution of one or more parts of the group consisted of：-F、-OH、- OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) and-N (C₁-C₆Alkyl)₂, and R²For H.

In certain embodiments, R²And R³Combination forms C₃-C₆Cycloalkyl.In certain embodiments, R²And R³Combination is formed Cyclopenta ring.In certain embodiments, R²And R³Combination forms cyclohexyl ring.In certain embodiments, R²And R³Combination forms 3 Member is to 7 circle heterocycles alkyl.In certain embodiments, R²And R³Combination forms pyrrolidines basic ring.In certain embodiments, R²And R³ Combination forms piperidines basic ring.In certain embodiments, R²And R⁶Combination forms pyrrolidine ring.In certain embodiments, R²And R⁶Group Conjunction forms piperidines basic ring.

In certain embodiments, R⁴And R⁵Respectively it independently is H, fluorine, chlorine, bromine, methyl, ethyl, propyl group, isopropyl ,-OH, first Epoxide, ethyoxyl, isopropoxy ,-CN or-CF₃.In certain embodiments, R⁴For H, fluorine, chlorine, bromine, methyl, ethyl, propyl group, different Propyl group ,-OH, methoxyl group, ethyoxyl, isopropoxy ,-CN or-CF₃, and R⁵For H.In certain embodiments, R⁴For fluorine, and R⁵For H。

In other embodiments, Formulas I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII compound is selected from the group consisted of：The fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes of (7R, 13R) -7- ethyls -11- - Azacyclotridecane -4 (5H) -one of 1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, (6R, 13R) -6- The fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges of ethyl -11--pyrazolo [4,3-f] [1,4,8,10] benzo oxa- Three azacyclotridecane -4 (5H) -one, the fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- second of (7S, 13R) -7- ethyls -11- Alkene bridge pyrazolo [4,3-f] [1,4,8,10] three azepines of benzo oxa--ring tridecane -4 (5H) -one, (6S, 13R) -6- ethyls - The fluoro- azepines of 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three of 11- Ring tridecane -4 (5H) -one, (7R, 13R) -11- fluoro- 7- (hydroxymethyl) -13- methyl -6,7,13,14- tetrahydrochysene -1,15- second Azacyclotridecane -4 (5H) -one of alkene bridge pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, the fluoro- 6- of (6S, 13R) -11- (hydroxymethyl) -13- methyl -6,7,13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- Three azacyclotridecane -4 (5H) -one, (7S, 13R) -11- fluoro- 7- (hydroxymethyl) -13- methyl -6,7,13,14- tetrahydrochysene -1, 15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10]-benzo oxa- three azacyclotridecane -4 (5H) -one, (6R, 13R) -11- Fluoro- 6- (hydroxymethyl) -13- methyl -6,7,13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo Oxa- three azacyclotridecane -4 (5H) -one, (7R, 13R) -11- fluoro- 7- (methyl fluoride) -13- methyl -6,7,13,14- tetrahydrochysenes - Azacyclotridecane -4 (5H) -one of 1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, (7S, 13R) - 11- fluoro- 7- (methyl fluoride) -13- methyl -6,7,13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzene And oxa- three azacyclotridecane -4 (5H) -one, (6S, 13R) -11- fluoro- 6- (methyl fluoride) -13- methyl -6,7,13,14- four Azacyclotridecane -4 (5H) -one of hydrogen -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, (7R, 13R) the fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3- of -7- [(dimethylamino) methyl] -11- F] [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one, (6S, 13R) -6- [(dimethylamino) methyl] -11- Fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] three azepines of benzo oxa--ring Tridecane -4 (5H) -one, the fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- of (7S, 13R) -7- (N-METHYLFORMAMIDE) -11- Azacyclotridecane -4 (5H) -one of ethylene bridge pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, (7R, 13R) -7- (N- first Base formamide) fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzos of -11- Oxa- three azacyclotridecane -4 (5H) -one, the fluoro- 13- methyl -6,7,13,14- four of (6R, 13R) -6- (difluoromethyl) -11- Azacyclotridecane -4 (5H) -one of hydrogen -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, (6S, 13R) the fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolos [4,3-f] of -6- (difluoromethyl) -11- [1,4, 8,10] benzo oxa- three azacyclotridecane -4 (5H) -one, fluoro- 13- methyl -6,7 of (7R, 13R) -7- (difluoromethyl) -11-, Azacyclotridecane -4 (5H) -one of 13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, Fluoro- 6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] the benzo oxa-s of (13R) -13- ethyls -11- Three azacyclotridecane -4 (5H) -one, the fluoro- 6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges of (7S, 13R) -7,13- diethyl -11- Pyrazolo [4,3-f] [1,4,8,10] three azepines of benzo oxa--ring tridecane -4 (5H) -one, (6S, 13R) -6,13- diethyl - The fluoro- azacyclo-s 13 of 6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three of 11- Alkane -4 (5H) -one, (13R) -11- fluoro- 13- (2- hydroxyethyls) -6,7,13,14- tetrahydrochysene -1,15- ethylene bridge pyrazolos [4,3- F] three azepines of [1,4,8,10] benzo oxa--ring tridecane -4 (5H) -one, the fluoro- 13- of (13R) -11- (2- fluoro ethyls) -6,7, Azacyclotridecane -4 (5H) -one of 13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, The fluoro- 13- of (13S) -11- (2- hydroxyl propyl- 2- yls) -6,7,13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolos [4,3-f] [1,4,8, 10] three azepines of benzo oxa--ring tridecane -4 (5H) -one, (7S, 13R) -11- fluoro- 7- (methoxy) -13- methyl -6, The azacyclotridecane -4 (5H) of 7,13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three - Ketone, the fluoro- 7- methyl isophthalic acids 3- of (7S, 13R) -11- (²H₃) methyl -6,7,13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolos [4,3-f] [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one, fluoro- 6,7,13,14- tetrahydrochysene -1 of (7R) -7- ethyls -11-, Azacyclotridecane -4 (5H) -one of 15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, the fluoro- 7- of (7R) -11- The azacyclotridecane of methyl -6,7,13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three - The fluoro- 7- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] of 4 (5H) -one, (7S) -11- Benzo oxa- three azacyclotridecane -4 (5H) -one, the fluoro- 6- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges of (6R) -11- Azacyclotridecane -4 (5H) -one of pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, fluoro- 6- methyl -6,7 of (6S) -11-, Azacyclotridecane -4 (5H) -one of 13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, (7S, 13R) -7,13- dimethyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] pyrido [2,3-l] [1, 4,8,10] oxa- three azacyclotridecane -4 (5H) -one, 7- methyl -6,7,14,15- tetrahydrochysenes -2H-3,5- (nitrence base methylenes Bridge) three azacyclotridecane -16 (13H) -one of pyrrolo- [3,4-f] [1,4,8,10] benzo oxa-, (13R) -11- fluoro- 13, 17- dimethyl -6,7,13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] three azepines of benzo oxa--ring The fluoro- 7,13,17- trimethyls -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridge pyrazoles of tridecane -4 (5H) -one, (7S, 13R) -11- And [4,3-f] [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one, (13R) -13- methyl -6,7,13,14- four Hydrogen -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] three azepines of benzo oxa--ring tridecane -4 (5H) -one, (13R) - The azepine of 13,17- dimethyl -6,7,13,14- tetrahydrochysene -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three Ring tridecane -4 (5H) -one, [the fluoro- 7- methyl -4- oxos -4,5,6,7,13,14- hexahydros -1,15- ethene of (7S, 13R) -11- Azacyclotridecane -13- the bases of bridge pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three] acetonitrile, (7S, 13R) -3- ethyls - Fluoro- 7,13- dimethyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] the benzo oxa-s three of 11- Fluoro- 7,13- dimethyl -6,7,14,15- tetrahydrochysenes -2H-3,5- (the nitrence bases of azacyclotridecane -4 (5H) -one, (7R, 13S) -9- Methylene bridge) pyrrolo- [3,4-f] [1,4,8,10] three azepines of benzo oxa--ring tridecane -16 (13H) -one, (3aR, 9R, 17aS) the fluoro- 9- methyl isophthalic acids of -7-, 2,3,3a, [b] pyrazolo of 9,10,17,17a- octahydro -16H-11,13- ethene bridged ring penta [4, 3-f] three azacyclotridecane -16- ketone of [1,4,8,10] benzo oxa-, the fluoro- 9- methyl isophthalic acids of (3aS, 9R, 17aR) -7-, 2,3, 3a, 9,10,17,17a- octahydro -16H-11,13- ethene bridged ring penta [b] pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three Azacyclotridecane -16- ketone, the fluoro- 9- methyl isophthalic acids of (3aR, 9R, 17aR) -7-, 2,3,3a, 9,10,17,17a- octahydros -16H- Azacyclotridecane -16- the ketone of 11,13- ethene bridged ring penta [b] pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, (4aS, 10R, 18aS) fluoro- 10- methyl -2,3,4,4a, 10,11,18,18a- octahydro -12,14- ethylene bridges dibenzo [b, l] pyrazoles of -8- And [4,3-f] [1,4,8,10] three azepines of oxa--ring tridecane -17 (1H) -one, the fluoro- 10- methyl of (4aR, 10R, 18aR) -8- - 2,3,4,4a, 10,11,18,18a- octahydro -12,14- ethylene bridges dibenzo [b, l] pyrazolo [4,3-f] [1,4,8,10] oxa- Three azacyclotridecane -17 (1H) -one, the fluoro- 9- methyl isophthalic acids of (3aS, 9R, 17aS) -7-, 2,3,3a, 9,10,17,17a- octahydros - Azacyclotridecane -16- the ketone of 16H-11,13- ethene bridged ring penta [b] pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three, Fluoro- 10- methyl -2,3,4,4a, 10,11,18,18a- octahydro -12,14- the ethylene bridges dibenzo of (4aS, 10R, 18aR) -8- [b, L] three azacyclotridecane -17 (1H) -one of pyrazolo [4,3-f] [1,4,8,10] oxa-, the fluoro- 9- first of (3aR, 9R, 17aS) -7- Base -1,2,3,3a, 9,10,17,17a- octahydro -16H-11,13- ethylene bridges pyrazolo [4,3-f] pyrrolo- [3,4-b] [1,4, 8,10] azacyclotridecane -16- ketone of benzo oxa- three, the fluoro- 9- methyl isophthalic acids of (3aS, 9R, 17aS) -7-, 2,3,3a, 9,10,17, The azacyclo- of 17a- octahydros -16H-11,13- ethylene bridges pyrazolo [4,3-f] pyrrolo- [3,4-b] [1,4,8,10] benzo oxa- three Fluoro- 14- methyl -7,8,14,15- tetrahydrochysenes -4H, 6H-1,16- the ethylene bridge -5,8- first bridges of tridecane -16- ketone, (8R, 14R) -12- Pyrazolo [4,3-g] [1,5,9,11] three azepines of the benzo oxa--ring tetradecane -4- ketone, fluoro- 14- methyl -7 of (8S, 14R) -12-, The azepine of 8,14,15- tetrahydrochysenes -4H, 6H-1,16- ethylene bridge -5,8- first bridge pyrazolos [4,3-g] [1,5,9,11] benzo oxa- three The fluoro- 15- methyl -6,7,8,9,15,16- hexahydros -4H-1,17- ethylene bridges -5,9- first of the ring tetradecane -4- ketone, (9R, 15R) -13- Azepine cyclopentadecane -4- the ketone of bridge pyrazolo [4,3-h] [1,6,10,12] benzo oxa- three, the fluoro- 15- methyl of (9S, 15R) -13- - 6,7,8,9,15,16- hexahydros -4H-1,17- ethylene bridges -5,9- first bridge pyrazolos [4,3-h] [1,6,10,12] benzo oxa- three Fluoro- 14- methyl -7,8,14,15- tetrahydrochysenes -4H, 6H-5,8- the second bridge -1,16- second of azepine-cyclopentadecane -4- ketone, (14R) -12- The azacyclo- tetradecane -4- the ketone of alkene bridge pyrazolo [4,3-g] [1,5,9,11] benzo oxa- three, (7S, 13R) -7- [(dimethylaminos Base) methyl] fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzos of -11- Oxa- three azacyclotridecane -4 (5H) -one, the fluoro- 13- methyl -7- of (7R, 13R) -11- [(methylamino) methyl] -6,7,13, 14- tetrahydrochysene -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] three azepines of benzo oxa--ring tridecane -4 (5H) -one, The fluoro- 13- methyl -7- of (7S, 13R) -11- [(pyrrolidin-1-yl) methyl] -6,7,13,14- tetrahydrochysene -1,15- ethylene bridge pyrazolos [4,3-f] [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one, the fluoro- 13- first of (7R, 13R) -7- ethyls -11- The azacyclo- of base -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] pyrido [3,2-l] [1,4,8,10] oxa- three The fluoro- 7,13- dimethyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridge pyrazolos of tridecane -4 (5H) -one, (7S, 13S) -11- Azacyclotridecane -4 (5H) -one of [4,3-f] pyrido [3,2-l] [1,4,8,10] oxa- three, (7S, 13R) -11- fluoro- 7, 13- dimethyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] pyrido [3,2-l] [1,4,8,10] oxa- Three azacyclotridecane -4 (5H) -one, (7S) -11- fluoro- N, 7- dimethyl -4- oxo -4,5,6,7,13,14- hexahydros -1,15- Azacyclotridecane -13- the formamides of ethylene bridge pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three and the fluoro- N of (7S) -11-, N, 7- trimethyl -4- oxos -4,5,6,7,13,14- hexahydro -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxygen Miscellaneous three azacyclotridecanes -13- formamides

Or its pharmaceutically acceptable salt.

Following representative formula I, I-1, Ia, Ib, Ic, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII's The illustrative embodiment of compound：

One of ordinary skill in the art will be appreciated that listed herein or explanation material is not detailed and this also may be selected A little other materials defined in the range of term.

Pharmaceutical composition

For therapeutic purposes, including the medical composition of compound described herein can further comprise one or more pharmaceutically Acceptable excipient.Pharmaceutically acceptable excipient is nontoxic and is biologically being suitable for the thing of administration individual in addition Matter.This kind of excipient contributes to administration compound described herein and can compatibility with active component.Pharmaceutically acceptable excipient Example include stabilizer, lubricant, surfactant, diluent, antioxidant, adhesive, colouring agent, swelling agent, emulsification Agent or flavor dressing agent.In a preferred embodiment, medical composition of the invention is aseptic composite.Medical composition can be used It is prepared by known to those skilled in the art or available mixed technology.

Present invention also contemplates that aseptic composite, the combination for the national and regional regulation for meeting keyholed back plate this based composition is included Thing.

Medical composition as described herein and compound can be formulated into suitable medical solvent or solution in carrier, emulsion, Suspension or dispersion liquid, or together with the solid carrier according to the conventional method for becoming known for preparing various formulations in art It is deployed into pill, lozenge, mouth containing ingot, suppository, anther sac, dragee, particle, powder, recovery powder or capsule.The present invention's Medical composition can be by being adapted to bang path (such as oral, parenteral, per rectum, intranasal, part or ocular route) or logical Cross suction administration.Preferably, composition is formulated for intravenous or be administered orally.

To be administered orally, the compounds of this invention can (such as lozenge or capsule) or solution, emulsion or suspension in solid form Liquid form provides.To prepare oral composition, the compounds of this invention can it is formulated with produce such as daily about 0.1mg to 1g or Daily about 1mg to 50mg or daily about 50 to 250mg or daily about 250mg to 1g dosage.Oral lozenge can include activity The mixture of composition and following pharmaceutically acceptable compatibility excipient, such as diluent, disintegrant, adhesive, lubricant, sweet tea Taste agent, flavor enhancement, colouring agent and preservative.It is adapted to inert filler to include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, breast Sugar, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, D-sorbite and the like.Exemplary liquid Oral excipient includes ethanol, glycerine, water and the like.Starch, Polyvinyl-pyrrolidone (PVP), starch glycolate NF Sodium, microcrystalline cellulose and alginic acid are exemplary disintegrant.Adhesive can include starch and gelatin.Lubricant is if there is can be Magnesium stearate, stearic acid or talcum.If necessary, lozenge can be coated with such as glycerin monostearate or distearin Material is to postpone absorption in the gastrointestinal tract, or can be coated with enteric coating.

Capsule for being administered orally includes hard gelatin capsule and Perle.To prepare hard gelatin capsule, activity into Dividing can mix with solid, semisolid or liquid diluent.Perle can be by by active component and water, oil (such as peanut Oil or olive oil), atoleine, the mixture of the monoglyceride of short chain fatty acids and two glyceride, polyethylene glycol 400 or the third two Alcohol is mixed to prepare.

Liquid for being administered orally can be suspension, solution, emulsion or syrup form or can be frozen in the form of desciccate Dry or presentation is with before the use with water or other suitable mediator recoveries.This kind of fluid composition optionally contains：Pharmaceutically Acceptable excipient, such as suspending agent (such as D-sorbite, methylcellulose, sodium alginate, gelatin, hydroxyethyl cellulose Element, carboxy methyl cellulose, aluminium stearate gel and the like)；Non-aqueous vehicle, such as oil (such as apricot kernel oil or warp point The coconut oil of level separation), propane diols, ethanol or water；Preservative (such as methyl p-hydroxybenzoate or propylparaben Or sorbic acid)；Wetting agent, such as lecithin；And flavor enhancement or colouring agent if necessary.

To carry out parenteral use, comprising intravenous, intramuscular, intraperitoneal, intranasal or subcutaneous route, medicament of the invention The aseptic aqueous solution of proper pH value and isotonicty can be buffered to or form of suspension or carried with parenteral acceptable oil form For.It is adapted to aqueous vehicles to include Ringer's solution (Ringer's solution) and isotonic sodium chloride.This kind of form can be with unit Formulation (such as ampoule or disposable syringe device), multiple dose form (such as the bottle of suitable dosage can be taken out) or available There is provided in the solid form or preconcentrate form for preparing injectable composite.In time in the range of several minutes to a couple of days, Illustrative infusion dosage is in the range of the mixture of about 1 to 1000 μ g/kg medicaments per minute and medical carrier.

To carry out intranasal, sucking or be administered orally, medical composition of the invention can be used for example also containing being adapted to carrier Spraying composite administration.The present composition can be formulated for suppository form per rectum administration.

To carry out local application, the compounds of this invention is preferably allocated as emulsifiable paste or ointment or suitable for the similar of local administration Mediator.To carry out local administration, the compounds of this invention can be with medical carrier with concentration of the medicine than mediator about 0.1% to about 10% Mixing.Another pattern of the medicament of the administration present invention can realize transdermal transfer using paster composite.

As used herein, term " treatment " covers " preventative " and " curative " treatment.Instruction is intended in " preventative " treatment The generation of disease, disease symptomses or Medical Condition is postponed, suppresses symptom or reduction disease or the symptom generation or multiple being likely to occur The risk of hair." curative " treatment is comprising the seriousness for reducing present illness, symptom or symptom or suppresses its deterioration.Therefore, control Treat comprising improvement present illness symptom or prevent its deterioration；Prevent other symptoms to occur；Improve or prevent the potential whole body of symptom Venereal disease because；Suppress illness or disease, such as the generation of containment illness or disease；Alleviate illness or disease；Illness or disease is set to disappear Move back；Symptom caused by alleviation disease or illness；Or stop the symptom of disease or illness.

Term " individual " refers to the mammalian subject for needing this kind for the treatment of, such as the mankind.

Exemplary disease includes cancer, pain, sacred disease, autoimmune disease and inflammation.Cancer include such as lung cancer, Colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, clear-cell carcinoma, stomach and esophagus-stomach cancer, spongioblastoma, head and neck cancer, inflammation Property myofibroblast tumour and polymorphy large celllymphoma.Pain includes the pain for example from any source or the cause of disease, The pain of pain, nerve pain comprising cancer pain, from chemotherapy, the pain from damage or other sources.It is autologous Immunological diseases include such as rheumatoid arthritis, Xiu Gelian syndromes (Sjogren syndrome), type i diabetes and wolf Sore.Exemplary sacred disease includes Alzheimer disease (Alzheimer's Disease), Parkinson's (Parkinson's Disease), amyotrophic lateral sclerosis and Huntington disease (Huntington's disease).Exemplary diseases associated with inflammation Include atherosclerosis, allergy and the inflammation for coming self-infection or damage.

In an aspect, compound of the invention and medical composition especially target tyrosine receptor kinase, especially MET, ALK, AXL, TRK and JAK.Therefore, these compounds and medical composition can be used for preventing, reverse, slow down or suppressing one Or the activity of these a variety of kinases.In a preferred embodiment, treatment method target on cancer.In other embodiments, method is used for Treat lung cancer or non-small cell lung cancer.

In the suppressing method of the present invention, " effective dose " means to be enough the amount for suppressing target albumen.Measure this kind of target Regulation can be performed by conventional method of analysis (such as analysis method described below).This kind of regulation is applied to a variety of situations, bag Containing ex vivo assay.In this kind of method, cell is preferably to have abnormal because MET, ALK, AXL, TRK and/or JAK are raised The cancer cell of signal transduction.

In the treatment method of the present invention, " effective dose " means to be generally sufficient to produce in the individual for needing this kind for the treatment of The amount or dosage of wanted treatment benefit.The effective dose or dosage of the compounds of this invention can by conventional method (such as modelling, agent Amount is incremented by or clinical test) consideration conventional factors (such as pattern or approach, the pharmacokinetics of medicament of dispensing or drug delivery The judgement of the seriousness and the course of disease, the health status of individual, symptom and weight and the treating physician that learn, infect) determine.Exemplary dose Amount is in about 0.1mg to 1g daily or about 1mg to 50mg or daily about 50 to 250mg or daily about 250mg to 1g scopes daily It is interior.Accumulated dose can be given with single or fractionated dose unit (such as BID, TID, QID).

After the disease of patient improves, dosage can be adjusted for prevention or maintaining treatment.For example, dispensing Dosage or frequency or both can change to drop to symptom to be maintained to be treated or prevented the level of effect.Certainly, if symptom Alleviate to appropriate level, then can stop treating.However, patient can require that long-term intermittent is treated in any recurrence of symptom. Patient may also need long-term continued treatment.

Drug regimen

Invention as described herein compound can be used for medical composition or side with one or more other active ingredient combinations Disease and illness as described herein are treated in method.Other active components, which include, relaxes the therapy for being used for disease expectancy target not The other therapies or medicament of good action.This kind of combination can be used to improve effect, improve Other diseases symptom, reduce one or more pairs Act on or reduce the compounds of this invention wants dosage.Other active components can be to the compounds of this invention in corresponding medical composition Middle administration can be contained in single medical composition together with the compounds of this invention.Other active components can be in the administration present invention Compound simultaneously, before or after administration.

Combination medicament includes known or finds that effectively treating disease and illness as described herein (includes and be directed to and the disease Relevant another target those activity) other active components.For example, composition of the invention and composite and control Treatment method can comprise additionally in other medicines or medicament, such as suitable for treating or alleviating target disease or related symptoms or symptom Other activating agents.For cancer indication, other this kind of medicaments including (but not limited to)：Kinase inhibitor, such as EGFR suppress Agent (such as Erlotinib (erlotinib), Gefitinib (gefitinib)), Raf inhibitor (such as Wei Luofeini (vemurafenib)), VEGFR inhibitor (such as Sutent (sunitinib)), ALK inhibitor (such as gram Zhuo replaces Buddhist nun)； Standard chemotherapeutic regimens medicament, such as alkylating agent, antimetabolite, antitumor antibiotics, topoisomerase enzyme inhibitor, platinum class medicine Thing, mitotic inhibitor, antibody, hormonotherapy or corticosteroid.For pain indication, it is adapted to combination medicament to include and disappears Scorching medicine, such as NSAID.The medical composition of the present invention can comprise additionally in one or more this kind of activating agents, and treatment method can be another Outer one or more this kind of activating agents for including administration effective dose.

Chemical synthesis

It is following general on it with reference to illustrative synthesis flow suitable for the Exemplary chemical entity of the inventive method Preparation method and the description of subsequent particular instance.Professional should be understood that, to obtain this paper various compounds, initial substance can be through suitable Work as selection, finally to be substituted with to carry by reaction process in the case of presence or absence of safeguard measure on demand Base, so as to obtain desired product.Or, it may be necessary to or need finally wanting the position utilization of substituent to pass through reaction The suitable group that flow is carried and replaced when appropriate through wanted substituent.In addition, one of ordinary skill in the art should be understood that it is following The conversion shown in flow can be compatible with the functionality of specific side base any order perform.

AbbreviationExample as described herein is used including (but not limited to) passing through following contracting known to those skilled in the art Write the material of description：

Universal method A.

Prepare (R) -5- ((1- (5- fluoro-2-hydroxyphenyls) ethyl) amino) pyrazolo [1,5-a] pyrimidine -3- Ethyl formates (A-1).

Step 1. prepare (R)-N- (the fluoro- 2- phenol methylenes of 5-) -2- methylpropane -2- sulfenamides (A-1-3) to (R) -2- methylpropanes -2- sulfenamides (Sigma-Aldrich, 20.00g, 165.02mmol, 1.00 equivalent) and the fluoro- 2- of 5- Hydroxy benzaldehyde (Sigma-Aldrich, 23.12g, 165.02mmol, 1.00 equivalent) is in dichloromethane (200.00mL) Cs is added in solution₂CO₃(161.30g, 495.06mmol, 3.00 equivalent).Mixture is stirred at ambient temperature 16 hours.It is logical Cross the addition water (200mL) at 0 DEG C and reactant mixture is quenched, then extracted with EtOAc (200mL × 4).With salt solution (500mL) The organic layer through merging is washed, through Na₂SO₄Dry, filtering and concentration.By silica gel tubing string with 20:1 to 1:1 petroleum ether/second Acetoacetic ester is purified by flash residue, obtains the A-1-3 (18.00g, 73.98mmol, 44.83% yield) of white solid-like.¹H NMR(CDCl₃, 400MHz) and δ ppm 8.66 (s, 1H), 7.19 (dt, J=2.4,5.2Hz, 2H), 7.03-6.96 (m, 1H), 1.29(s,9H)。

Step 2. prepares (R)-N- ((R) -1- (5- fluoro-2-hydroxyphenyls) ethyl) -2- methylpropane -2- sulfenamides (A-1-4R) is at -65 DEG C, in N₂Under, to A-1-3 (6.00g, 24.66mmol, 1.00 equivalent) in THF (50.00mL) MeMgBr THF solution (2M, 61.7mL, 123.30mmol, 5.00 equivalent) is added dropwise in solution.Then mixture is set to heat up To environment temperature and stir 18 hours.Be quenched reactant mixture by adding water (20mL) at 0 DEG C, and with EtOAc (20mL × 3) mixture is extracted.The organic layer through merging is washed with salt solution (50mL), through Na₂SO₄Dry, filter and concentrate under reduced pressure.It is logical Silica gel is crossed with 50/1 to 1:1 petrol ether/ethyl acetate is purified by flash residue, obtains A-1-4R (Rf：0.5, PE:EA=1: 1) (1.8g, 28% yield) and A-1-4S (Rf：0.4, PE:EA=1:1).A-1-4R's¹HNMR(CDCl₃,400MHz)δ9.34 (s, 1H), 6.76 (dd, J=2.8,8.8Hz, 1H), 6.54 (dt, J=2.9,8.5Hz, 1H), 6.38 (dd, J=4.8, 8.8Hz, 1H), 5.27 (d, J=8.0Hz, 1H), 4.36 (quin, J=7.2Hz, 1H), 1.52 (d, J=7.0Hz, 3H), 1.29 (s,9H).A-1-4S's¹HNMR(CDCl₃, 400MHz) and δ 8.81 (s, 1H), 6.88 (dd, J=2.6,9.2Hz, 1H), 6.84- 6.76 (m, 1H), 6.76-6.70 (m, 1H), 4.75-4.63 (m, 1H), 4.26 (d, J=4.5Hz, 1H), 1.58 (d, J= 6.8Hz,3H),1.27(s,9H)。

The preparation of step 3. (R) -2- (1- amino-ethyls) -4- fluorophenols (A-1-5) stirs A-1-4R in environment temperature The solution of (1.80g, 6.94mmol, 1.00 equivalent) in HCl/EtOAc (20.00mL, 4N) 2 hours, and then concentration mixing Thing, obtain the A-1-5 (1.10g, 5.74mmol, 82.70% yield) of white solid HCl salt.¹HNMR(DMSO-d₆, 400MHz) δ 10.24 (s, 1H), 8.48 (br.s., 3H), 7.31 (dd, J=2.9,9.7Hz, 1H), 7.05-6.99 (m, 1H), 6.98-6.93 (m, 1H), 4.59-4.45 (m, 1H), 1.46 (d, J=6.8Hz, 3H).

The preparation of step 4. 5- oxo -4H- pyrazolos [1,5-a] pyrimidine -3- Ethyl formates (A-1-7) at 20 DEG C, N₂Under, to 5- amino -1H- pyrazoles -4- Ethyl formates (150.00g, 1.08mmol) and (E) -3- ethoxy-c -2- olefin(e) acid ethyl esters Cs is disposably added in the mixture of (292.16g, 2.03mol) in DMF (3.2L)₂CO₃(656.77g, 2.02mol). 110 DEG C are stirred mixture 6 hours.TLC(PE:EtOAc=1:1) display reaction is completed.Mixture is cooled to 20 DEG C and passes through silicon Diatomaceous earth pad filters.With ethyl acetate (3 × 30mL) filter wash cake.It filtrate be added to H₂PH=is acidified in O (2L) and with HOAc 4.Gained sediment is filtered, obtains the A-1-7 (173.00g, 834.98mmol, 86.36% yield) of white solid：¹H NMR (400MHz,DMSO-d₆) δ 8.54 (d, J=7.91Hz, 1H), 8.12 (s, 1H), 6.13 (d, J=7.91Hz, 1H), 4.27 (q, J=7.11Hz, 2H), 1.28 (t, J=7.09Hz, 3H).

Step 5：The preparation of 5- chlorine pyrazolo [1,5-a] pyrimidine -3- formic acid esters (A-1-8) is at 20 DEG C, in N₂Under, to A- 1-7 (158.00g, 762.59mmol) adds POCl in the mixture in MeCN (1.6L)₃(584.64g, 3.81mol). 100 DEG C are stirred mixture 2 hours.TLC(PE:EA=1:1) display reaction is completed.Mixture is cooled to 20 DEG C, and at 0 DEG C by Part is poured into ice-water (5000mL) and stirred 20 minutes.Filtering precipitate and drying, obtain the A-1-8 of white solid (110.00g, 487.52mmol, 63.93% yield)：¹H NMR(400MHz,DMSO-d₆) δ 9.33 (d, J=7.28Hz, 1H), 8.66 (s, 1H), 7.41 (d, J=7.15Hz, 1H), 4.31 (q, J=7.15Hz, 2H), 1.32 (t, J=7.09Hz, 3H).

Step 6. (R) -5- ((1- (5- fluoro-2-hydroxyphenyls) ethyl) amino) pyrazolo [1,5-a] pyrimidine -3- formic acid second To A-1-5 (1.10g, 7.09mmol, 1.00 equivalent) and A-1-8, (1.60g, 7.09mmol, 1.00 work as the preparation of ester (A-1) Amount) DIEA (5.50g, 42.53mmol, 6.00 equivalent) is added in solution in n-BuOH (30.00mL).In 120 DEG C of stirrings Mixture 2 hours.Reactant mixture is quenched by adding water (20mL) at ambient temperature, and is extracted with EtOAc (20mL × 3) Take.The organic layer of merging is washed with salt solution (50mL), through Na₂SO₄Dry, filtering and concentration.Pass through column chromatography (SiO₂, oil Ether/ethyl acetate=10/1 to 1:3) residue is purified, obtains A-1 (1.15g, 3.31mmol, 46.69% of white solid Yield, the purity of ee ＞ 97%).

Prepare (R) -5- ((1- (5- fluoro-2-hydroxyphenyls) propyl group) amino) pyrazolo [1,5-a] pyrimidine -3- Ethyl formates (A-2) follows universal method A and prepares A-2 using EtMgBr in step 2.

Prepare (R)-N- ((R) -1- (5- fluoro-2-hydroxyphenyls) -3- hydroxypropyls) -2- methylpropane -2- sulfenamides (A-3-5).

Step 1. is at 25 DEG C, and into drying equipment, Zn (6.72g, 102.75mmol, 5.00 equivalent) is in anhydrous THF TMSCl (446.51mg, 4.11mmol, 0.20 equivalent) is added dropwise in suspension in (50mL).Stir mixture 10 minutes, Then 40~50 DEG C are heated under a nitrogen.Into mixture through be added dropwise within 20 minutes 2- bromoacetates (10.30g, 61.65mmol, 3.00 equivalents) solution in anhydrous THF (500mL), subsequent reaction stirred 30 minutes at 40~50 DEG C. Cool down the solution that black mixture is to 0 DEG C and addition A-1-3 (5.00g, 20.55mmol, 1.00 equivalent) is in THF (500mL). Reaction stirred 2 hours at 25 DEG C, with saturation NH₄Cl (100mL) is quenched and extracted with EtOAc (300mL × 3).Use water (300mL × 2) and salt solution (300mL × 2) wash the organic layer through merging, through anhydrous Na₂SO₄Dry, filtering and concentration.Pass through Silica gel tubing string (100-200 meshes) is purified by flash residue with 50/1,10/1 petrol ether/ethyl acetate, obtains white solid The A-3-4S (4.35g, 13.13mmol, 63.87% yield) and A-3-4R (0.52g, 16.35% yield) of body shape.A-3-4S 's¹HNMR:(400MHz, chloroform-d) δ 8.77 (s, 1H), 6.90 (dd, J=3.0,9.0Hz, 1H), 6.86-6.80 (m, 1H), 6.78-6.72 (m, 1H), 5.33 (d, J=5.0Hz, 1H), 4.97-4.90 (m, 1H), 4.21-4.14 (m, 2H), 3.03-2.94 (m,1H),2.93-2.84(m,1H),1.29-1.24(m,12H)；A-3-4R's¹HNMR:(400MHz, chloroform-d) δ 9.43 (s, 1H), 6.79 (dd, J=2.9,8.7Hz, 1H), 6.45 (dt, J=3.0,8.5Hz, 1H), 6.16 (dd, J=4.6,8.9Hz, 1H), 5.53 (d, J=9.8Hz, 1H), 4.65 (dt, J=5.3,9.8Hz, 1H), 4.13-4.07 (m, 2H), 3.01 (dd, J= 9.7,15.4Hz, 1H), 2.63 (dd, J=5.1,15.4Hz, 1H), 1.29-1.24 (m, 12H).

Step 2. is at 0 DEG C, to A-3-4R (500.00mg, 1.51mmol, 1.00 equivalent) in anhydrous THF (5.00mL) Solution in add LiBH portionwise₄(131.44mg, 6.04mmol, 4.00 equivalent).It is small that mixture 2 is stirred at ambient temperature When.With saturation NH₄Reactant mixture is quenched in Cl (50mL), then by EtOAc (100mL) dilute and with EtOAc (100mL × 3) extract.The organic layer through merging is washed with salt solution (50mL), through Na₂SO₄Dry, filtering and concentration.Obtain white solid-like A-3-5 (360.00mg, 1.24mmol, 82.39% yield).¹HNMR (400MHz, chloroform-d) δ 9.13 (br.s., 1H), 6.79 (dd, J=2.8,8.7Hz, 1H), 6.53 (dt, J=3.0,8.5Hz, 1H), 6.27 (dd, J=4.7,8.7Hz, 1H), 5.19 (d, J=9.2Hz, 1H), 4.42 (q, J=7.7Hz, 1H), 3.71 (td, J=5.7,10.8Hz, 1H), 3.61-3.46 (m, 1H), 2.27-2.09 (m, 1H), 1.97 (dt, J=6.5,13.0Hz, 1H), 1.28 (s, 9H).

Prepare (R) -5- ((1- (5- fluoro-2-hydroxyphenyls) -3- hydroxypropyls) amino) pyrazolo [1,5-a] pyrimidine -3- Ethyl formate (A-3) follows universal method A and prepares A-3 using A-3-5 in step 3.

Prepare (S) -2- (1- amino -2- hydroxy-2-methyls propyl group) -4- fluorophenols (A-4-6)

Step 1. is at 0 DEG C, in N₂Under, to the bromo- 4- fluorophenols of 2- (Sigma-Aldrich, 13.00g, 68.06mmol, 1.00 equivalents) last in solution in THF (100.00mL) 5 hours addition NaH (2.72g, 60%, in oil, 68.06mmol, 1.00 equivalents), then add MOMCl (3.02g, 37.51mmol, 0.55 equivalent).It is stirred at 16 DEG C Thing 10 hours, it is quenched by water (200ml) and is extracted with EtOAc (100mL × 3).Having through merging is washed with salt solution (200ml) Machine layer, through Na₂SO₄Dry and concentrate, obtain the A-4-1 (9.00g, 38.29mmol, 56.26% yield) in oily.

Step 2. is at -78 DEG C, in N₂Under, in 30 minutes, to A-4-1 (14.00g, 59.56mmol, 1.00 equivalent) I-PrMgCl-LiCl THF solution (1.3M, 45.82mL, 1.00 are added dropwise in solution in anhydrous THF (140.00mL) Equivalent).Mixture is set to be maintained 1.5 hours after being warming up to 25 DEG C, and at -30 DEG C, in N₂Under, gained is mixed in 20 minutes Thing is added dropwise in solution of the diethyl oxalate (43.39g, 296.90mmol, 5.00 equivalent) in THF (140ml).Make Mixture maintains 1.5 hours after being warming up to 25 DEG C.TLC displaying initial substances are completely depleted.Quenched by being slowly added water (200mL) Go out reactant and stirring 10 minutes.Organic layer is separated, and with ethyl acetate (500mL × 3) aqueous phase extracted.Use saturated brine (500mL) washs the organic layer through merging, uses anhydrous Na₂SO₄Dry, filter and concentrate in a vacuum.Used by silica gel chromatography 50/1 to 10/1 petrol ether/ethyl acetate is purified by flash residue, obtain in yellow oily A-4-2 (5.70g, 23.53mmol, 39.6% yield).¹HNMR (400MHz, chloroform-d) δ 7.56 (dd, J=3.2,8.2Hz, 1H), 7.30-7.24 (m, 1H), 7.23-7.18 (m, 1H), 5.15 (s, 2H), 4.48-4.34 (m, 2H), 3.48 (s, 3H), 1.40 (t, J=7.2Hz, 3H)。

Step 3. at ambient temperature, in N₂Under, to A-4-2 (5.70g, 22.25mmol, 1.00 equivalent) and (R) -2- first Base propane -2- sulfenamides (4.05g, 33.38mmol, 1.50 equivalent) disposably add in the mixture in THF (50.00mL) Add Ti (OEt)₄(7.61g, 33.38mmol, 1.50 equivalent).Heat the mixture to 70 DEG C and stir 12 hours.TLC displaying startings Material is completely depleted.Cooling mixture concentrates to environment temperature and in a vacuum at 45 DEG C.Residue is poured into water (100mL) In.With ethyl acetate (300mL × 3) aqueous phase extracted.The organic phase through merging is washed with salt solution (300mL), uses anhydrous Na₂SO₄It is dry It is dry, filter and concentrate in a vacuum.Pass through silica gel chromatography (tubing string height：250mm, diameter：100mm, 100-200 mesh silicon Glue, petrol ether/ethyl acetate=20/1,5/1) purifying residue, obtain in yellow oily A-4-3 (3.20g, 8.90mmol, 40.02% yield).¹HNMR (400MHz, chloroform-d) δ 7.56 (dd, J=3.2,8.2Hz, 1H), 7.30-7.24 (m, 1H), 7.23-7.18 (m, 1H), 5.15 (s, 2H), 4.48-4.34 (m, 2H), 3.48 (s, 3H), 1.40 (t, J=7.2Hz, 3H).

Step 4. is at 0 DEG C, in N₂Under, to A-4-3 (3.00g, 8.69mmol, 1.00 equivalent) in MeOH (30.00mL) In solution in add NaBH portionwise₄(361.44mg, 9.56mmol, 1.10 equivalent).Reactant mixture is set to be warming up to environment temperature Maintained 2 hours after degree.Reactant is slowly quenched with frozen water (50mL), is then extracted with DCM (100mL × 3).Use salt solution (100mL) washs the organic phase through merging, through anhydrous Na₂SO₄Dry, filter and concentrate in a vacuum.Pass through column chromatography (SiO₂, petrol ether/ethyl acetate=10/1 to 3:1) purify residue, obtain in oily A-4-4S (1.20g, 4.98mmol, 38% yield, the first elution fraction) and A-4-4R (600mg, the 19%, second elution fraction).A-4-4S's¹HNMR (400MHz, chloroform-d) δ 7.11 (dd, J=4.4,9.0Hz, 1H), 7.04 (dd, J=3.2,8.8Hz, 1H), 7.00-6.93 (m, 1H), 5.33 (d, J=8.0Hz, 1H), 5.18 (s, 2H), 4.41 (d, J=8.0Hz, 1H), 4.23-4.12 (m, 2H), 3.49(s,3H),1.23-1.17(m,12H).A-4-4R's¹HNMR (400MHz, chloroform-d) δ 7.12 (dd, J=4.4, 8.8Hz, 1H), 7.02-6.94 (m, 2H), 5.41 (d, J=4.0Hz, 1H), 5.16 (s, 2H), 4.61 (d, J=4.0Hz, 1H), 4.29-4.13(m,2H),3.50(s,3H),1.24-1.17(m,12H)。

Step 5. is at -78 DEG C, in N₂Under, to A-4-4S (600.00mg, 1.66mmol, 1.00 equivalent) in THF MeMgBr (3M Et are added dropwise in solution in (10.00mL)₂O solution, 4.43mL, 8.00 equivalents).At ambient temperature Stir mixture 12 hours.Pour the mixture into saturation NH₄In Cl (20mL) and stir 10 minutes.With ethyl acetate (50mL × 3) aqueous phase extracted and the organic phase through merging is washed with salt solution (50mL), uses anhydrous Na₂SO₄Dry, filter and dense in a vacuum Contracting, obtain the A-4-5 (542.00mg, 1.56mmol, 93.97% yield) in yellow solid.¹HNMR (400MHz, chloroform- D) δ 7.13 (dd, J=4.4,9.0Hz, 1H), 7.08-7.02 (m, 1H), 6.96-6.89 (m, 1H), 5.24-5.15 (m, 2H), 4.67-4.35(m,2H),3.50(s,3H),1.35(s,3H),1.21(s,9H),1.10(s,3H)。

Step 6. by compound A-4-5 (540.00mg, 1.55mmol, 1.00 equivalent) be dissolved in HCl/ dioxanes (4N, In 5.00mL), at ambient temperature in N₂Lower stirring 2 hours.TLC displaying reactions are completed.Methanol (20mL) is added to mixing In thing and stir 10 minutes at ambient temperature.Solvent is then removed under reduced pressure, obtains A-4-6, and it is without further purification It is used for next step.

Prepare (S) -5- ((1- (5- fluoro-2-hydroxyphenyls) -2- hydroxy-2-methyls propyl group) amino) pyrazolo [1,5-a] Pyrimidine -3- Ethyl formates (A-4) prepares A-4 using A-4-6 in step 3 by universal method A.

Prepare 2- (1- amino second -1- bases) -3- pyridones (A-6-3)

Step 1. to compound A-6-1 (8.00g, 58.33mmol, 1.00 equivalent) and potassium carbonate (24.19g, 175.00mmol, 3.00 equivalents) add in solution in methanol (50.00mL) hydroxylamine hydrochloride (5.31g, 75.83mmol, 1.30 equivalent).Mixture is stirred at 25 DEG C 12 hours.TLC (petrol ether/ethyl acetate=1/1) displaying initial substances are complete Exhaust and find a new spot.Mixture is poured into H₂Extracted in O (100mL) and by ethyl acetate (100mL × 3). Organic layer is washed by salt solution (100mL), through anhydrous sodium sulfate drying and concentration, obtains the compound A-6- in yellow solid 2 (5.50g, 36.15mmol, 61.97% yields).

Step 2. to compound A-6-2 (5.50g, 36.15mmol, 1.00 equivalent) and zinc powder (9.46g, 144.59mmol, 4.00 equivalents) ammonium chloride (11.15g, 144.59mmol, 4.00 equivalent) is added in solution in ethanol (10.00mL).In 0- Mixture is stirred at 25 DEG C 18 hours.TLC (petrol ether/ethyl acetate=1/1) displaying initial substance it is completely depleted and find one Individual new blotch.Filter mixture and concentration filtrate, obtain in yellow solid compound A-6-3 (4.00g, 28.95mmol, 80.08% yield).¹HNMR:(400MHz, DMSO-d6) δ 7.75 (d, J=4.4Hz, 1H), 7.27 (d, J= 8.0Hz, 1H), 7.17 (dd, J=4.4,8.0Hz, 1H), 4.51 (q, J=6.4Hz, 1H), 1.28 (d, J=6.4Hz, 3H)

Follow and use 2- (amino methyl) -4- fluorophenols and 5- chlorine pyrazolo [1,5-a] pyrimidine -3- for A-1 program Ethyl formate prepares A-5 as initial substance.

Follow and use A-6-3 and 5- chlorine pyrazolo [1,5-a] pyrimidine -3- Ethyl formates as starting for A-1 program Material prepares A-6.

Universal method B.

The fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolos of preparation (7S, 13R) -7- ethyls -11- [4, 3-f] [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one (1) and

The fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolos [4,3-f] of (6S, 13R) -6- ethyls -11- [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one (2)

Step 1：To (S) -2- ethyls oxirane (1.00g, 13.87mmol) in H₂O(3.08mL)、MeOH NaN is added in solution in (21.58mL) and THF (3.08mL)₃(4.51g, 69.35mmol) and NH₄Cl (1.71g, 31.90mmol).Heating response mixture 4 hours at 75 DEG C, are subsequently cooled to environment temperature, then add water (100mL). Mixture is extracted with ethyl acetate (3 × 50mL), and the extract through merging is washed with salt solution (50mL), through Na₂SO₄Dry and Concentrate under reduced pressure.1-1 and 2-1 crude mixture is used in next step without further purification.

Step 2. adds PPh into solution in THF (30.00mL) of 1-1 and 2-1 (1.35g, 11.73mmol)₃ (4.61g, 17.60mmol), and stirring reaction solution 65 hours at ambient temperature.TLC, which shows conversion, to be completed.To reaction solution Middle addition H₂O (3.00g, 166.48mmol), and stir mixture 7 hours, then add Boc₂O (3.21g, 14.72mmol) and Solution of the triethylamine (2.38g, 23.56mmol) in THF (30mL).Reaction stirred 19 hours at ambient temperature, pass through It is added in water (50mL) and is quenched, is extracted with DCM (3 × 50mL), use Na₂SO₄Dry and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (40g), the hexane solution of 0-35% ethyl acetate) provide 1-2 the first elution fraction (1.379g, 61.86% yield).LC-MS m/z 212.2(M+Na)⁺；¹H NMR (500MHz, DMSO-d6) δ ppm 6.62 (br t, J= 5.73Hz, 1H) 4.50 (d, J=5.16Hz, 1H) 3.34 (br s, 1H) 2.87-2.96 (m, 1H) 2.78-2.86 (m, 1H), 1.38-1.44 (m, 1H) 1.37 (s, 9H) 1.15-1.26 (m, 1H) 0.84 (t, J=7.45Hz, 3H).Second elution fraction is 1-2 And 2-2 mixture (0.625g, 28.03% yield).

Step 3. is at -20 DEG C to 1-2 (467.00mg, 2.47mmol) and CH₃SO₂Cl (325.38mg, 2.84mmol) in Buddhist nun Xi Shi alkali (957.67mg, 7.41mmol) is permitted in addition in solution in DCM (12.35mL).Reactant is set to be warming up to environment temperature Degree, stir 22 hours, be then quenched by being added in water (50mL).Mixture is extracted with DCM (3 × 50mL), uses Na₂SO₄It is dry It is dry and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (24g), the hexane solution of 0-35% ethyl acetate) provides 1-3 (623.90mg, 2.33mmol, 94.48% yield).LC-MS m/z 290.1(M+Na)⁺。

Step 4. is to 1-3 (116.46mg, 0.436mmol) and A-1 (120.00mg, 0.348mmol) in DMF (1.74mL) In solution in add K₂CO₃(240.82mg,1.74mmol).Heat mixture under agitation at 80 DEG C 24 hours, be cooled to Environment temperature, diluted with DCM (3mL), filtered by syringe filter and concentrated under reduced pressure.Flash chromatography (ISCO systems, Silica gel (12g), the hexane solution of 0-40% ethyl acetate) provide 1-4 and 2-4 mixture (59.40mg, 0.115mmol, 33.06% yield).LC-MS m/z 516.3(M+H)⁺。

Step 5：To 1-4 and 2-4 mixture (59.40mg, 0.115mmol) in MeOH (3.03mL) and THF LiOH H is added in solution in (1.49mL)₂O solution (2M, 1.00mL).Mixture is heated at 70 DEG C 3 hours, be cooled to Environment temperature, with water and methanol dilution, then it is transferred to acidity with HCl/water solution (2M, 1.00mL) and is quenched.With DCM (3 × 5mL) Mixture is extracted, uses Na₂SO₄Dry and concentrate under reduced pressure.Dried residue is overnight under a high vacuum, is then dissolved in DCM In (4.0mL), then add HCl Isosorbide-5-Nitrae-dioxane (4M, 2.0mL) and stir 2 hours at ambient temperature.Depressurizing It is lower to concentrate mixture and dry under a high vacuum.Solid dissolving is added in DMF (2mL) and DCM (10mL) and into solution FDPP (50.76mg, 0.132mmol) and perhaps Buddhist nun Xi Shi alkali (74.23mg, 0.574mmol).Stir mixture 2 hours, then use Na₂CO₃The aqueous solution (2M, 12mL) is quenched.Stir mixture 5 minutes, then extracted with DCM (4 × 10mL).Use Na₂SO₄Dry Extract through merging and concentrate under reduced pressure.Follow-up flash chromatography (ISCO systems, silica gel (12g), 0-10% methanol/bis- Chloromethanes) pure 1 (3.56mg), 2 (3.83mg) and 1 and 2 mixture (23.94mg), gross production rate 73.85% are provided.

Compound 3 to 8 is prepared using universal method B.In step 1, (R) -2- ethyls oxirane is used for 3 and 4, (S) -2- ((methoxymethoxy) methyl) oxirane is used for 5 and 6, then carries out the acid deprotection of acetal, and by (R) - 2- ((methoxymethoxy) methyl) oxirane is used for 7 and 8, then carries out the acid deprotection of acetal.

Universal method C.

Prepare (7R, 13R) -11- fluoro- 7- (methyl fluoride) -13- methyl -6,7,13,14- tetrahydrochysene -1,15- ethylene bridge pyrazoles And [4,3-f] [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one (9)

Into solution of 5 (3.00mg, the 0.0081mmol) in DCM (0.161mL) add Deoxo-Fluor (3.58mg, 0.0162mmol).Mixture is stirred 30 minutes, with saturation NaHCO₃Solution (3mL) is quenched, and is extracted with DCM (3 × 3mL), uses Na₂SO₄Dry and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (12g), 0-17.5% ethanol/methylenes) 9 (1.30mg, 43.1% yields) are provided.

Use universal method C with compound 7 and 8 for initial substance prepare compound 10 and 11 respectively.

Universal method D.

Prepare the fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- of (7R, 13R) -7- [(dimethylamino) methyl] -11- Ethylene bridge pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one (12)

Step 1. adds the high iodine of Dai Si-Martin into solution of 5 (11.00mg, the 0.0296mmol) in DCM (0.60mL) Alkane (Dess-Martin Periodinane) (25.13mg, 0.0592mmol).Mixture is stirred at ambient temperature 30 minutes, With saturation NaHCO₃Solution (3mL) is quenched, and uses DCM:MeOH (5 × 3mL, 1:1) extract, use Na₂SO₄Dry and dense under reduced pressure Contracting.The flash chromatography (ISCO systems, silica gel (12g), 0-22.5% ethanol/methylenes) of residue, obtains aldehyde 12-1 (8.10mg, 0.0219mmol, 74.04% yield).LC-MS m/z 370.2(M+H)⁺。

Step 2. added into solution of the 12-1 (5.00mg, 0.0135mmol) in MeOH dimethylamine (2M, 0.034mL).Mixture 2 hours is heated at 60 DEG C, and is cooled to environment temperature, then add sodium borohydride (1.54mg, 0.0406mmol) and stir 1 hour.THF solution (2M, 1mL) and the excessive NaBH4 for adding a part of dimethylamine again are anti-to drive It should complete.Heating mixture is overnight at 45 DEG C and is concentrated to dry.Residue is dissolved in MeOH and adds HCl/water solution (2M, 0.40mL).Stir mixture 30 minutes, then add the NaOH aqueous solution (2M, 0.45mL), extracted with DCM (4 × 3mL). Use Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (adds during compound loads 0.060mL TEA) (ISCO systems, silica gel (12g), 0-25% methanol is in dichloromethane) provide the 12 of white solid (1.89mg, 0.0474mmol, 35.03% yield).

Universal method E.

Prepare the fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- of (6S, 13R) -6- [(dimethylamino) methyl] -11- Ethylene bridge pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one (13)

To 6 (7.20mg, 0.0194mmol) and CH at -20 DEG C₃SO₂Cl (8.88mg, 0.0776mmol) is in DCM Buddhist nun Xi Shi alkali (37.59mg, 0.291mmol) is permitted in addition in solution in (0.50mL).Reactant is warming up to environment temperature, stir Mix 1 hour, be then quenched by adding saturated bicarbonate solution (2mL).Mixture is extracted with DCM (3 × 3mL), uses Na₂SO₄ Dry and be concentrated to drying under reduced pressure.The THF solution (2M, 1.98mL) of dimethylamine is added in residue flask.70 Mixture is heated at DEG C 6 hours and concentrated under reduced pressure.(ISCO systems, C18 (30g gold col), contain flash chromatography The aqueous solution of 0.035%TFA 0-100% acetonitriles) provide tfa salt form 13 (2.93mg).

Universal method F.

Prepare (7S, 13R) -11- fluoro- N, 13- dimethyl -4- oxo -4,5,6,7,13,14- hexahydro -1,15- ethylene bridges Azacyclotridecane -7- the formamides (14) of pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three and the fluoro- N of (7R, 13R) -11-, 13- dimethyl -4- oxos -4,5,6,7,13,14- hexahydro -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxygen Miscellaneous three azacyclotridecanes -7- formamides (15)

To 3- amino -2 hydroxy propanoic acid (3.50g, 33.30mmol, 1.00 equivalent) in Isosorbide-5-Nitrae-dioxanes at 0 DEG C NaOH (1.33g, 33.30mmol, 1.00 equivalent) is added dropwise in solution in (30.00mL) in H₂It is molten in O (30.00ml) Liquid.Mixture is stirred at 0 DEG C 1 hour, then add (Boc)₂O (8.29g, 37.97mmol, 1.14 equivalent).Make mixture It is warming up to environment temperature and stirs 11 hours, is quenched by adding HCl/water solution (1M, 5mL) at 0 DEG C with adjusting to pH~6, Then extracted with EtOAc (20mL × 3).The organic layer through merging is washed with salt solution (50mL), through Na₂SO₄Dry, filtering, and Decompression is lower to be concentrated, and obtains 3- ((tert-butoxycarbonyl) amino) -2 hydroxy propanoic acid (3.50g), it is i.e. straight without further purification Connect use.¹H NMR(400MHz,CDCl₃)δ7.93(br.s.,1H),5.41(br.s.,1H),4.32(br.s.,1H),3.65- 3.40(m,2H),1.42(s,9H)。

Step 2. to 3- ((tert-butoxycarbonyl) amino) -2 hydroxy propanoic acids (1.00g, 4.87mmol, 1.00 equivalent) in Methylamine (1.32g, 19.49mmol, 4.00 equivalent, hydrochloric acid are added in solution in DCM (24.00mL) and DMF (24.00mL) Salt), EDCI (1.40g, 7.31mmol, 1.50 equivalent), HOBt (987mg, 7.31mmol, 1.50 equivalent) and 4- methyl morpholines (2.96g, 29.24mmol, 6.00 equivalent).Mixture is stirred at ambient temperature 16 hours, then concentration.Use citric acid (100mL) dilutes residue and extracted with EtOAc (200mL × 2).With saturation NaHCO₃The aqueous solution (100mL) washing is through merging Organic layer, through MgSO₄Dry, filter and concentrate in a vacuum, obtain (2- hydroxyls -3- (the methyl ammonia of white solid-like Base) -3- oxopropyls) t-butyl carbamate (980.00mg, 4.49mmol, 92.20% yield).¹H NMR(CDCl₃, 400MHz) δ 7.03 (br.s., 1H), 5.41-5.14 (m, 2H), 4.19 (d, J=2.8Hz, 1H), 3.65-3.55 (m, 1H), 3.54-3.44 (m, 1H), 2.85 (d, J=5.2Hz, 3H), 1.45 (s, 9H).

Step 3. is at 0 DEG C, to (2- hydroxyls -3- (methylamino) -3- oxopropyls) t-butyl carbamate 15 minutes addition TEA are lasted in the agitating solution of (980.00mg, 4.49mmol, 1.00 equivalent) in DCM (60.00mL) (2.27g, 22.45mmol, 5.00 equivalent), 4- toluene sulfonyl chlorides (1.71g, 8.98mmol, 2.00 equivalent) and catalytic amount DMAP (54.86mg, 449.03 μm of ol, 0.10 equivalent).Reaction stirred 12 hours at ambient temperature, by adding citric acid (100mL) is quenched, and is then diluted with EtOAc (100mL) and is extracted with EtOAc (100mL × 3).With saturation NaHCO₃(100mL) The organic layer through merging is washed, through anhydrous sodium sulfate drying, filters and concentrates under reduced pressure.Pass through column chromatography (SiO₂, stone Oily ether/ethyl acetate=10/1 to 1:1) purify residue, obtain white solid-like 14-1 (1.05g, 2.82mmol, 62.80% yield).¹H NMR(CDCl₃, 400MHz) and δ 7.84 (d, J=8.0Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 6.38 (br.s., 1H), 4.87 (t, J=4.8Hz, 1H), 4.77 (br.s., 1H), 3.62-3.40 (m, 2H), 2.80 (d, J= 4.8Hz,3H),2.47(s,3H),1.41(s,9H)。

Step 4. is to A-1 (75.00mg, 0.218mmol) and 14-1 (89.23mg, 0.240mmol) in DMF (1.1mL) Solution in add K₂CO₃(150.52mg, 1.09mmol).Maintain 75 hours after heating the mixture to 70 DEG C under agitation, daily K is added again₂CO₃And 14-1 is completed with driving to react.Reactant is cooled down to environment temperature, is diluted with DCM (3mL), passes through syringe mistake Filter is filtered and concentrated under reduced pressure.(ISCO systems, silica gel (12g), the hexane of 0-100% ethyl acetate are molten for flash chromatography Liquid) 14-2 (65.00mg, 0.119mmol, 54.8% yield) is provided.LC-MS m/z545.3(M+H)⁺。

Step 5. at ambient temperature, to 14-2 (65.00mg, 0.119mmol) in MeOH (2.98mL) and THF The LiOH aqueous solution (2.0M, 2.01mL) is added in solution in (2.01mL).Mixture is heated at 70 DEG C 2 hours, be cooled to Environment temperature, with water and methanol dilution, then it is transferred to acidity with HCl/water solution (2.0M, 2.01mL) and is quenched.With DCM (3 × Mixture 5mL) is extracted, uses Na₂SO₄Dry, concentrate and dry under a high vacuum overnight under reduced pressure.DCM is added into residue (3.00mL), then add HCl Isosorbide-5-Nitrae-dioxane (4M, 2.00mL).It is small that mixture 1.5 is stirred at ambient temperature When, concentrate and dry under a high vacuum under reduced pressure.Into residue add DMF (4.00mL) and FDPP (50.34mg, 0.131mmol), then Buddhist nun Xi Shi alkali (76.97mg, 0.596mmol) is permitted in addition.It is small that mixture 1.5 is stirred at ambient temperature When, use Na₂CO₃The aqueous solution (2M, 4.0mL) is quenched, and stirs 5 minutes.Mixture is extracted with DCM (4 × 10mL), and is used Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (12g), 0-17.5% Ethanol/methylene) pure 14 (2.29mg) of offer are used as the first elution fraction and 15 (3.63mg) are used as last elution fraction.In Between elution fraction (12.8mg) be 14 and 15 mixture.

Universal method G.

Prepare the fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridge pyrroles of (6R, 13R) -6- (difluoromethyl) -11- Azoles simultaneously [4,3-f] [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one (16), (6S, 13R) -6- (difluoro first Base) fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] the benzo oxa-s three of -11- The fluoro- 13- methyl -6,7,13,14- four of azacyclotridecane -4 (5H) -one (17) and (7R, 13R) -7- (difluoromethyl) -11- Hydrogen -1,15- ethylene bridges pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one (18)

Step 1. is to 3- amino -1,1- difluoro propan-2-ol hydrochlorides (150.29mg, 1.16mmol) and Boc- acid anhydrides Buddhist nun Xi Shi alkali (449.76mg, 3.48mmol) is permitted in addition in the solution of (316.46mg, 1.45mmol) in THF (5.8mL).Stir Mix mixture 18 hours, and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (12g), 0-40% ethyl acetate Hexane solution) providing (3,3- bis- fluoro- 2- hydroxypropyls) t-butyl carbamate, (195.20mg, 0.924mmol, 79.8% are produced Rate).

Step 2. at -78 DEG C to (3,3- bis- fluoro- 2- hydroxypropyls) t-butyl carbamate (195.20mg, 0.924mmol), TosCl (211.44mg, 1.11mmol) and DMAP (5.65mg, 0.462mmol) are molten in DCM (4.6mL) Buddhist nun Xi Shi alkali (358.33mg, 2.77mmol) is permitted in addition in liquid.Reactant is warming up to environment temperature, stir 15 hours, then It is quenched by being added in water (15mL).Mixture is extracted with DCM (3 × 10mL), through Na₂SO₄Dry and concentrate under reduced pressure. Flash chromatography (ISCO systems, silica gel (12g), the hexane solution of 0-25% ethyl acetate) provides 4- toluene sulfonic acide 3- [(uncles Butoxy carbonyl) amino] -1,1- difluoro propyl- 2- base esters (240.60mg, 0.658mmol, 71.25% yield).

Step 3. to A-1 (75.00mg, 0.218mmol) and 4- toluene sulfonic acides 3- [(tert-butoxycarbonyl) amino] -1, 1- difluoro propyl- 2- base esters (95.50mg, 0.261mmol) add K in the solution in DMF (1.09mL)₂CO₃(150.52mg, 1.09mmol).Heat mixture under agitation at 80 DEG C 18 hours, be cooled to environment temperature, diluted, passed through with DCM (3mL) Syringe filter is filtered and concentrated under reduced pressure.Flash chromatography (ISCO systems, silica gel (12g), 0-50% ethyl acetate oneself Alkane solution) the first elution fraction is provided, it be 16-1 (26.00mg, 0.0484mmol, 22.21% yield) that it, which differentiates, and 17-1 and The second elution fraction (26.7mg) of 18-1 form of mixtures.

Step 4. 16-1 is converted into 16 using the method for step 5 in universal method B.17-1 and 18-1 mixture is turned The mixture of macrocyclic compound is turned to, with flash chromatography (ISCO systems, silica gel (12g), 0-7.5% ethanol/methylenes) Separation, obtains 17 and 18.

Compound 19 and 22 to 24 is used in (2- chloroethyls) t-butyl carbamate alternative steps 1 according to universal method F 14-1 and A-2-A-4 prepare.

Compound 20 and 21 uses the A-1 in A-2 alternative steps 4 to prepare according to universal method B.

Compound 25 uses the 2- second in (2R) -2- (methoxy) oxirane alternative steps 1 according to universal method B It is prepared by hexadecyl ethylene oxide.

Universal method H.

The fluoro- 7- methyl isophthalic acids 3- of preparation (7S, 13R) -11- (²H₃) methyl -6,7,13,14- tetrahydrochysene -1,15- ethylene bridge pyrazoles And [4,3-f] [1,4,8,10] benzo oxa- three azacyclotridecane -4 (5H) -one (26)

Step 1. is at 20 DEG C, in N₂Under, to 26-1 (10.00g, 71.37mmol, 1.00 equivalent) and (R) -2- methyl-props Alkane -2- sulfenamides (8.65g, 71.37mmol, 1.00 equivalent) disposably add in the mixture in DCM (500.00mL) Cesium carbonate (69.76g, 214.11mmol, 3.00 equivalent), then stirred 12 hours at 50 DEG C.Cool down mixture to 20 DEG C and Concentrated in decompression at 45 DEG C.Residue is poured into water (300mL).With ethyl acetate (500mL × 3) aqueous phase extracted, close And organic phase and washed with saturated brine (500mL), through anhydrous sodium sulfate drying, filtering and concentrate in a vacuum, obtain remnants Thing, by petroleum ether wet-milling, obtain the 26-2 (15.00g, 61.65mmol, 86.38% yield) of white solid-like.¹HNMR (400MHz,CDCl₃) δ 10.85 (s, 1H), 8.64 (s, 1H), 7.21-7.14 (m, 2H), 6.99 (dd, J=4.4,10.0Hz, 1H),1.27(s,9H)。

Step 2. is to (R)-(2- hydroxypropyls) t-butyl carbamate (5.00g, 28.54mmol, 1.20 equivalent) and 26- 2 (5.79g, 23.78mmol, 1.00 equivalents) are in toluene/THF (15mL, v/v=1:1) PPh is added in the mixture in₃ (7.49g, 28.54mmol, 1.20 equivalent).Reactant mixture is cooled down to about 0 DEG C, and lasts 10 minutes and DIAD is added dropwise (5.77g, 28.54mmol, 5.55mL, 1.20 equivalent).Mixture is set to be warming up to 25 DEG C, and stir about is after ten minutes, then will 15ml toluene and 15ml THF are added in thick orange solution.Mixture is stirred at 25 DEG C 24 hours.It is dense in a vacuum Contracting reactant mixture and pass through column chromatography (petroleum ether:Ethyl acetate=20/1 to 5/1) purifying residue, obtain white The 26-3 (11.00g, 19.23mmol, 80.84% yield, 70% purity) of solid-like.¹HNMR(400MHz,CDCl₃)δ8.95 (s, 1H), 7.65 (dd, J=2.8,8.8Hz, 1H), 7.21-7.10 (m, 1H), 7.00 (br dd, J=4.0,8.8Hz, 1H), 5.08(br s,1H),4.57(br s,1H),3.45(br s,1H),3.36-3.22(m,1H),1.43(s,9H),1.30(br D, J=6.4Hz, 3H), 1.25 (br s, 9H)

Step 3. is at -10 DEG C by CD₃MgI (1M, 22.5mL) is added to 26-3 (3.00g, 7.49mmol) and MgBr₂· Et₂In solution of the O (12.7g, 45mmol) in MeTHF (37.5mL).Reactant is set slowly to be warming up to 0 DEG C through 3 hours, then By being added to saturation NH₄It is quenched in Cl solution (50mL).Mixture is extracted with DCM (3 × 50mL), uses Na₂SO₄Dry and Decompression is lower to be concentrated.Flash chromatography (ISCO systems, silica gel (40g), the hexane solution of 0-50% ethyl acetate) provides 26-4 (1.72g, 4.10mmol, 54% yield) and 26-5 (970mg, 2.31mmol, 30% yield).

Step 2. is by I₂(117mg, 462 μm of ol) are added to 26-5 (970mg, 2.31mmol) in THF (9.96mL) and water Solution in (2.04mL).Heating response thing is concentrated and dried under a high vacuum, obtain to maintaining 6 hours after 50 DEG C under reduced pressure To thick material 26-6.

Step 3. to thick 26-6 and 5- chlorine pyrazolo [1,5-a] pyrimidine -3- Ethyl formates (521mg, 2.31mmol) in Buddhist nun Xi Shi alkali (750mg, 5.8mmol) is permitted in addition in solution in EtOH (12mL).After heating the mixture to 60 DEG C under agitation Maintain 20 hours.Reactant is cooled down to environment temperature, by being added to full NaHCO₃Quenched in solution (25mL) and water (75mL) Go out and extracted with DCM (3 × 50mL).Use Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (40g), the hexane solution of 0-40% ethyl acetate) provides 26-7, and (894mg, 1.77mmol, 76% are produced Rate, through 2 steps).LC-MS m/z 505.3(M+H)⁺。

Step 4. is molten in MeOH (40mL) and THF (10mL) to 26-7 (894mg, 1.77mmol) at ambient temperature The LiOH aqueous solution (2.0M, 15mL) is added in liquid.Mixture is heated at 70 DEG C 22 hours, be cooled to -20 DEG C, then use HCl The aqueous solution (2.0M, 15.1mL) is transferred to acidity and is quenched.Mixture is extracted with DCM (3 × 50mL), uses Na₂SO₄Dry, under reduced pressure Concentrate and dry under a high vacuum overnight.Into residue add DCM (30mL), then add HCl diethyl ether solution (2M, 10mL).Mixture is stirred at ambient temperature 20 hours, concentrate and dry under a high vacuum under reduced pressure.To DMF (20mL), 1/3 and FDPP of the thick material is sequentially added in DCM (100mL) and the perhaps solution of Buddhist nun Xi Shi alkali (3.71g, 28.70mmol) The 1/3 of (603.21mg, 1.57mmol), it is subsequently agitated for mixture 1 hour.Addition is carried out 2 times again, and is stirred at ambient temperature Final mixture 18 hours, uses Na₂CO₃The aqueous solution (2M, 100mL) is quenched and stirred 5 minutes.It is mixed with DCM (3 × 50mL) extractions Compound, use Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (40g), 0- 8.75% ethanol/methylene) 26 (446mg, 79% yields) are provided.

Universal method I.

Preparation 7- methyl -6,7,14,15- tetrahydrochysenes -2H-3,5- (nitrence base methylene bridge) pyrrolo- [3,4-f] [1,4,8, 10] benzo oxa- three azacyclotridecane -16 (13H) -one (33)

Step 1. at 0 DEG C by triethylamine (1.10g, 10.9mmol) be added to 2- (1- amino-ethyls) phenol (499mg, 3.64mmol) and in solution of the TFAA (841mg, 4.0mmol) in DCM (18.2mL).The reaction stirred at 0 DEG C 2 hours, then it is quenched by being added in 0.5M HCl (100mL).Mixture is extracted with DCM (150mL).With 0.5M HCl (3 × 100mL) washing extract, use Na₂SO₄Dry and concentrate under reduced pressure.Dried residue under a high vacuum, obtain 33-1 (809.3mg, 3.47mmol, 95% yield).

Step 2. by 33-1 (550mg, 2.36mmol) and (2- hydroxyethyls) t-butyl carbamate (760mg, 4.72mmol) mix and from DCM:Toluene azeotropic drying.It will be re-dissolved in through dry mixture in DCM (1.50mL) And by PPh₃(1.27g, 4.84mmol) is added in solution.Stirring mixture is completely dissolved until all substances.Cool down solution DIAD (1.03g, 5.07mmol) is slowly added in pole to 0 DEG C and under agitation.Make that reactant is warming up to room temperature and stirring is 13 small When.Reactant is quenched by being poured into water (100mL), and is extracted with DCM (3 × 75mL).Use Na₂SO₄Dry the extraction through merging Take thing and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (24g), the hexane solution of 5-20% ethyl acetate) carries For 33-2 (655mg, 1.74mmol, 74% yield).

Step 3. is molten in MeOH (4.80mL) and H2O (1.20mL) to 33-2 (421mg, 1.12mmol) at room temperature K is added in liquid₂CO₃(309mg, 2.24mmol).Heating response thing is then cooled down and pours into 0.4M to maintaining 2.5 hours after 60 DEG C In NaOH solution (50mL), and extracted with DCM (3 × 50mL).Use Na₂SO₄Dry the extract through merging and dense under reduced pressure Contracting.Dried residue under a high vacuum, obtain 33-3 (227.8mg, 812 μm of ol, 72% yield).

Step 4. adds 33-4 at 0 DEG C into mixtures of the NaH (28mg, 1.18mmol) in DMF (4.06mL) (200mg, 812 μm of ol).Stir mixture 30 minutes, then add SEMCl (176mg, 1.06mmol).It is warming up to reactant Room temperature and stirring 2.5 hours, be then quenched by being added in water (25mL).Mixture is extracted with DCM (3 × 15mL), is used Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (12g), 0-50% second The hexane solution of acetoacetic ester) 33-5 (261.9mg, 696 μm of ol, 86% yield) is provided.

Step 5. is to 33-3 (75mg, 267 μm of ol), 33-5 (103mg, 267 μm of ol), DMG (8.3mg, 80 μm of ol) and K₂CO₃In the de gassed solution of (92mg, 668 μm of ol) in DMSO (1.34mL) add CuI (7.6mg, 40μmol).Heating response thing is poured into water (25mL) and extracted with DCM (3 × 15mL) to maintaining 4.5 hours after 100 DEG C.With Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (12g), 0-40% second The hexane solution of acetoacetic ester) 33-6 (30.2mg, 51.5 μm of ol, 19% yield) is provided.

Step 6. is molten in MeOH (3mL) and THF (1mL) to 33-6 (30.2mg, 51.5 μm of ol) at ambient temperature The LiOH aqueous solution (2.0M, 1mL) is added in liquid.Mixture is heated at 70 DEG C 45 minutes, be cooled to -20 DEG C, then use HCl/water Solution (2.0M, 1.1mL) is transferred to acidity and is quenched.Mixture is extracted with DCM (3 × 5mL), uses Na₂SO₄Dry, concentrate under reduced pressure And dry under a high vacuum.Thick material is dissolved in DCM (4mL), then adds HCl diethyl ether solution (2M, 2mL).In ring Mixture is stirred at a temperature of border 2 hours, concentrate and dry under a high vacuum under reduced pressure.Thick material is dissolved in DMF (1.0mL) And in DCM (4.0mL), and sequentially Buddhist nun Xi Shi alkali (33mg, 256 μm of ol) and FDPP (20.7mg, 54 μm of ol) are permitted in disposable addition. Reaction stirred 4 hours, then use 2M Na₂CO₃Solution (5mL) is quenched.Stir mixture 5 minutes, then with DCM (4 × 10mL) extract.Use Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (12g), the hexane solution of 0-100% ethyl acetate) 33-7 (13.9mg, 30.6 μm of ol, 59% yield) is provided.

33-7 (13.9mg, 30.6 μm of ol) is dissolved in DCM (1.00mL) and TFA (1.00mL) by step 7..Stirring is mixed Compound 30 minutes is untill all initial substances exhaust.Concentrated reaction solution is to drying and common with toluene (1mL) under reduced pressure Boil drying.Residue is re-dissolved in DCM (1.00mL) and MeOH (0.5mL) and adds NH₄OH (18M, 150 μ L).Stirring Solution 15 minutes and concentrate under reduced pressure.(ISCO systems, silica gel (12g), the dichloromethane of 0-15% methanol are molten for flash chromatography Liquid) 33 (4.9mg, 15 μm of ol, 49% yields) are provided.

Universal method J.

Prepare [the fluoro- 7- methyl -4- oxos -4,5,6,7,13,14- hexahydros -1,15- ethylene bridge pyrazoles of (7S, 13R) -11- And azacyclotridecane -13- the bases of [4,3-f] [1,4,8,10] benzo oxa- three] acetonitrile (38)

Step 1. is in N₂It is lower to Zn (3.02g, 46.24mmol, 3.75 equivalent) and 2- bromoacetonitriles (3.70g, 30.83mmol, 2.50 equivalents) TMSCl (254.52mg, 2.34mmol, 0.19 equivalent) is added dropwise in solution in THF (20.00mL). Mixture is stirred at 0 DEG C to maintaining 2 hours after 20 DEG C.Then A-1-3 (3.00g, 12.33mmol, 1.00 equivalent) is added to Mixture is stirred in mixture and at 50 DEG C 12 hours.TLC(PE:EtOAc=1:2) displaying reaction is carried out good.Then, lead to Cross water (20mL) mixture is quenched and is extracted with EtOAc (50mL*5), organic layer is washed by salt solution (50mL), through Na₂SO₄It is dry It is dry.Pass through column chromatography (SiO₂, petrol ether/ethyl acetate=10/1 to 1:5) residue is purified, obtains white solid-like 38-1 (260mg, PE:EtOAc=1:2, Rf=0.5) and 38-2 (441mg, PE:EtOAc=1:2, Rf=0.4).¹H NMR (400MHz,CDCl₃, 38-1) and δ 9.60 (s, 1H), 6.78 (dd, J=3.0,8.3Hz, 1H), 6.49 (dt, J=3.1,8.5Hz, 1H), 6.17 (dd, J=4.6,8.9Hz, 1H), 5.62 (d, J=10.2Hz, 1H), 4.45 (dt, J=4.6,10.3Hz, 1H), 3.12 (dd, J=10.5,17.0Hz, 1H), 2.65 (dd, J=4.7,17.0Hz, 1H), 1.38 (s, 9H)；¹H NMR (400MHz,CDCl₃, 38-2) and δ 9.10 (br.s., 1H), 6.92 (dq, J=3.0,8.7Hz, 2H), 6.81 (dd, J=4.6, 8.7Hz,1H),4.83-4.71(m,2H),3.11-3.02(m,2H),1.31(s,9H)。

Step 2. is by 38-1 (100.00mg, 351.68 μm of ol) and (R)-(2- hydroxypropyls) t-butyl carbamate (123.25mg, 703.36 μm of ol) are mixed and from DCM:Toluene azeotropic drying.Mixture is re-dissolved in DCM In (200.00 μ L) and by PPh₃(189.10mg, 720.94 μm of ol) are added in solution.Mixture is stirred until all substances It is completely dissolved, is subsequently cooled to 0 DEG C.Into solution, DIAD (145.78mg, 720.94 μm of ol, 141.53 μ are slowly added in pole L), mix simultaneously.Reactant is warming up to room temperature, stir 19 hours, be quenched and use by being added in water (4 times of solvent volumes) DCM (3 × 3mL) is extracted.Use Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (ISCO systems, Silica gel (12g), the hexane solution of 0-100% ethyl acetate), obtain 38-3 (58.8mg, 37% yield).

The reactions steps 2-4 that 38-3 is followed in universal method H is converted into 38.

Universal method K

Prepare ((S) -2- (2- ((R) -1- amino-ethyls) -4- fluorophenoxies)-propyl group) t-butyl carbamate (40-5)

Step 1. is at 0 DEG C to 40-1 (500.00g, 3.24mol, 1.00 equivalent), (R)-(2- hydroxypropyls) amino first Tert-butyl acrylate (851.57g, 4.86mol, 1.50 equivalent) and PPh₃(1.27kg, 4.86mol, 1.50 equivalent) is in dichloromethane DEAD (902.79g, 5.18mol, 940.41mL, 1.60 equivalent) is added dropwise in solution in (1.5L).Stirred at 25 DEG C Solution 4 hours.TLC instructions detect a new blotch with larger polarity, and initial substance is completely depleted.By petroleum ether (1.5L) is added in mixture, subsequent to cross filter solid, removes the solvent of filtrate and by column chromatography (SiO₂, petroleum ether/ Ethyl acetate=20/1 to 10:1) residue is purified, 40-2 (680.00g, 2.18mol, 67.28% of the oily that obtains taking on a red color Yield).¹H NMR (400MHz, chloroform-d) δ 7.38 (dd, J=3.2,8.8Hz, 1H), 7.13 (ddd, J=3.2,7.2, 8.8Hz, 1H), 6.97 (dd, J=4.0,8.8Hz, 1H), 5.06 (br.s., 1H), 4.63-4.52 (m, 1H), 3.52-3.39 (m, 1H), 3.38-3.27 (m, 1H), 2.59 (s, 3H), 1.42 (s, 9H), 1.32 (d, J=6.4Hz, 3H).

Step 2. is at 20 DEG C, in N₂Under, to (R) -2- methylpropane -2- sulfenamides (219.98g, 1.82mol, 1.50 equivalents), diethylene glycol dimethyl ether (162.35g, 1.21mol, 172.71mL, 1.00 equivalent) and 40-2 (376.00g, 1.21mol, 1.00 equivalents) disposable addition four in mixture in THF (1.88L) and 2- methyltetrahydrofurans (1.88L) Ethanolato-titanium (552.03g, 2.42mol, 501.85mL, 2.00 equivalent).Mixture is stirred at 60 DEG C 12 hours.TLC is shown About 15% initial substance is remaining.Mixture is cooled down to 20 DEG C.Add water (2L).With ethyl acetate (2000mL × 3) aqueous phase extracted. The organic phase through merging is washed with saturated brine (1L), through anhydrous Na₂SO₄Dry, filter and concentrate in a vacuum, obtain in red The 40-3 (520.00g, thick material) of color oily, it is used for next step without further purification.

Step 3. is at -50 DEG C to 40-3 (520.00g, 1.25mol, 1.00 equivalent) in THF/H₂O(3.82L/78mL) In solution in add NaBH₄(142.37g, 3.76mol, 3.00 equivalent), makes reactant be warming up to 25 DEG C, then at 25 DEG C Stirring 12 hours.TLC displaying initial substances are completely depleted.Water (1L) is added in mixture and extracted with EtOAc (2L × 2) Take.Organic layer is washed with saturation NaCl (1L) and through Na₂SO₄Dry.Remove solvent and pass through column chromatography (SiO₂, oil Ether/ethyl acetate=20/1 to 10:1) residue is purified, obtains 40-4 (270.00g, 570.40mmol, 45.47% yield).¹H NMR (400MHz, chloroform-d) δ 7.06 (dd, J=3.2,9.2Hz, 1H), 6.95 (dt, J=3.2,8.4Hz, 1H), 6.80 (dd, J=4.4,9.2Hz, 1H), 6.70 (br.s., 1H), 4.93 (d, J=6.0Hz, 1H), 4.57-4.46 (m, 1H), 3.68- 3.65 (m, 1H), 3.59-3.57 (m, 1H), 3.22-3.10 (m, 1H), 1.47 (d, J=6.8Hz, 3H), 1.40 (s, 9H), 1.27-1.25(m,3H),1.22(s,9H)。

Step 4. is at 25 DEG C, in N₂It is lower to 40-4 (270.00g, 570.40mmol, 1.00 equivalent) and molecular iodine H is added in the solution of (28.95g, 114.08mmol, 22.98mL, 0.20 equivalent) in THF (2.16L)₂O(540.00mL)。 Mixture is stirred at 50 DEG C 3 hours.TLC displaying initial substances are completely depleted.Mixture is concentrated, obtains white solid-like 40-5 (330.00g, thick material).LCMS:m/z 313.2(M+H⁺)。¹H NMR (400MHz, chloroform-d) δ 7.08 (dd, J= 2.8,9.4Hz,1H),6.91-6.79(m,2H),5.72(br.s.,1H),4.55-4.32(m,2H),3.52-3.41(m,1H), 3.31-3.19 (m, 1H), 1.42 (s, 9H), 1.38 (d, J=6.8Hz, 3H), 1.29 (d, J=6.0Hz, 3H).

Universal method L.

Prepare the fluoro- 9- methyl isophthalic acids of (3aR, 9R, 17aS) -7-, 2,3,3a, 9,10,17,17a- octahydro -16H-11,13- second Azacyclotridecane -16- the ketone (41) of alkene bridged ring penta [b] pyrazolo [4,3-f] [1,4,8,10] benzo oxa- three

Step 1. is to (1S, 2S) -2- amino cyclopentyl -1- alcohol (41-1) hydrochloride (500.00mg, 3.63mmol) and three second Amine (1.10g, 10.89mmol, 1.51mL) adds Boc in the solution in MeOH (18.15mL)₂O (1.58g, 7.26mmol). Reaction stirred 22 hours, is concentrated under reduced pressure.Flash chromatography (ISCO systems, silica gel (24g), 0-50% ethyl acetate Hexane solution) 41-2 (714.2mg, 3.55mmol, 97.76% yield) is provided.

Step 2. mixes 41-2 (100.00mg, 496.87 μm of ol) and A-1 (171.09mg, 496.87 μm of ol) And from DCM:Toluene azeotropic drying.Mixture is re-dissolved in DCM (248.43 μ L) and by PPh₃(136.84mg, 521.71 μ Mol) it is added in solution.Stirring mixture is completely dissolved until all substances.Pole slowly add DIAD (105.50mg, 521.71 μm of ol, 102.43 μ L), mix simultaneously.Reaction stirred 16 hours, be then quenched by being added in water (4mL) and Extracted with DCM (3 × 3mL).Use Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (ISCO systems System, silica gel (12g), the hexane solution of 0-50% ethyl acetate) 41-3 (17.6mg, 6.7% yield) is provided.

The step 4 that step 3. 41-3 is followed in universal method H is converted into 41.

Universal method M.

The fluoro- 13- methyl -6,7,13,14- tetrahydrochysenes -1,15- ethylene bridges pyrazolos of preparation (7R, 13R) -7- ethyls -11- [4, 3-f] pyrido [3,2-l] [1,4,8,10] oxa- three azacyclotridecane -4 (5H) -one (58)

Step 1：By MeMgBr Et at -78 DEG C₂O solution (3M, 6.45mL) be added to 58-1 (1.00g, 6.45mmol) in the solution in THF (32mL).Reactant is slowly warming up to 5 DEG C through 4 hours, be subsequently cooled to -78 DEG C and By adding saturation NH₄The Cl aqueous solution (20mL) is quenched.Mixture is set to be warming up to room temperature and be extracted with DCM (3 × 10mL).With Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (24g), 0-50% second The hexane solution of acetoacetic ester) 58-2 (1.10g, 6.43mmol, 100% yield) is provided.

Step 2：The solution of DMSO (753mg, 9.65mmol, 685 μ L) in DCM (5mL) is added dropwise at -78 DEG C Into solution of the ethanedioly chloride (1.22g, 9.65mmol, 827 μ L) in DCM (15mL).Agitating solution 20 minutes, then dropwise Add solution of the 58-2 (1.10g, 6.43mmol) in DCM (8mL).Reaction stirred 20 minutes, is then added dropwise TEA (3.25g, 32mmol, 4.46mL).Reactant is slowly warming up to room temperature, stir 2.5 hours and by being added to water (100mL) In be quenched.Mixture is extracted with DCM (3 × 25mL), uses Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Quickly Chromatography (ISCO systems, silica gel (24g), the hexane solution of 0-40% ethyl acetate) offer 58-3 (1.01g, 5.97mmol, 92% yield).

Step 3：To 58-3 (1.01g, 5.97mmol), (S) -2- methylpropane -2- sulfenamides (1.00g, 8.25mmol) and diethylene glycol dimethyl ether (801mg, 5.97mmol, 852 μ L) is in THF (6.0mL) and MeTHF (6.0mL) Ti (OEt) is added in solution₄(2.59g, 11.34mmol, 2.37mL).Mixture is heated at 60 DEG C 4 hours, be cooled to room temperature And it is quenched by being added in water (100mL).Mixture is extracted with DCM (3 × 50mL), and uses Na₂SO₄Dry extract and Decompression is lower to be concentrated.Flash chromatography (ISCO systems, silica gel (24g), the hexane solution of 5-30% ethyl acetate) provides 58-4 (1.31g, 4.81mmol, 80% yield).

Step 4：By NaBH at -78 DEG C₄(546mg, 14.4mmol) is added to 58-4 (1.31g, 4.81mmol) and H₂O In the solution of (260mg, 14.43mmol, 260 μ L) in THF (24mL).Make that reactant is slowly warming up to room temperature and stirring is 18 small When.Reactant is cooled to -78 DEG C and reactant sequentially is quenched with MeOH (3mL) and water (5mL), then with 2M HCl regulations pH Value is further diluted with water (75mL) and extracted with DCM (3 × 75mL) until neutrality.Use Na₂SO₄Dry the extract through merging And concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (40g), the hexane solution of 30-60% ethyl acetate) provides 56-5 (758.1mg, 2.76mmol, 57% yield) and 58-6 (414.9mg, 1.51mmol, 31% yield).

Step 5：To 58-5 (757mg, 2.76mmol) in THF (11.5mL) and H₂I is added in solution in O (2.30mL)₂ (140mg, 552 μm of ol).Mixture is heated at 50 DEG C 9 hours, then concentrate under reduced pressure, obtain 58-7.Under a high vacuum Dry compound and use as former state.

Step 6：To 58-7 (469.7mg, 2.76mmol) and 5- chlorine pyrazolo [1,5-a] pyrimidine -3- formic acid esters (778mg, 3.45mmol) Buddhist nun Xi Shi alkali (2.96g, 22.9mmol, 4.0mL) is permitted in addition in the solution in EtOH (14.0mL).At 80 DEG C Lower heated solution 64 hours.Mixture is concentrated under reduced pressure.Flash chromatography (ISCO systems, silica gel (40g), 50-100% second The hexane solution of acetoacetic ester) 58-8 (871.4mg, 2.42mmol, 87% yield) is provided.

Step 7：Into solution of the 58-8 (869.65mg, 2.42mmol) in EtOH (15.0mL) add HCl Isosorbide-5-Nitrae- Dioxane (4M, 15.0mL).75 DEG C are heated the mixture to, stirs 6 hours and concentrates under reduced pressure.Flash chromatography [dress It is loaded with containing Et₃N DCM (200 μ L)] (ISCO systems, silica gel (24g), the dichloromethane solution of 0-10% methanol) offer 58- 9 (736.1mg, 2.13mmol, 88% yields).

Step 8：By 58-9 (100mg, 289 μm of ol) and (S)-(2- hydroxybutyls) t-butyl carbamate (68.5mg, 362 μm of ol) mix and from DCM:Toluene azeotropic drying.Residue is re-dissolved in DCM (150 μ L) and by PPh₃ (99mg, 376 μm of ol) are added in solution.Stirring mixture is completely dissolved until all substances, and DIAD is slowly added in pole (76mg, 376 μm of ol, 73.9 μ L), is mixed simultaneously.Mixture is heated at 35 DEG C 2 hours, be cooled to room temperature and stir 3 days.Instead Answer thing to be quenched by being added in water (4mL) and extracted with DCM (3 × 4mL).Use Na₂SO₄Dry the extract through merging and Decompression is lower to be concentrated.Flash chromatography (ISCO systems, silica gel (12g), the hexane solution of 0-60% ethyl acetate) provides 58-10 (105.8mg, 204 μm of ol, 70% yield).

Step 9. is at ambient temperature to 58-10 (105.8mg, 204 μm of ol) in MeOH (4mL) and THF (1.5mL) The LiOH aqueous solution (2.0M, 1.5mL) is added in solution.Mixture is heated at 70 DEG C 3 hours, be cooled to -20 DEG C, then use HCl/water solution (2.0M, 1.6mL) is transferred to acidity and is quenched.Mixture is extracted with DCM (3 × 5mL), uses Na₂SO₄Dry, depressurizing It is lower to concentrate and dry under a high vacuum.Thick material is dissolved in DCM (4mL), then adds HCl Isosorbide-5-Nitrae-dioxane (4M, 3mL).Mixture is stirred at ambient temperature 15 hours, concentrate and dry under a high vacuum under reduced pressure.Thick material is molten Solution is in DMF (2.0mL) and DCM (8.0mL), and sequentially Buddhist nun Xi Shi alkali (264mg, 2.05mmol, 357 μ L) is permitted in disposable addition And FDPP (98mg, 255 μm of ol).Reaction stirred 3 hours, then use 2M Na₂CO₃Solution (5mL) is quenched.Stir mixture 5 Minute, then extracted with DCM (3 × 10mL).Use Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography Method (ISCO systems, silica gel (12g), the dichloromethane solution of 0-10% methanol) provides 58 (49.3mg, 133 μm of ol, 65% productions Rate).

Universal method N.

Prepare (7S) -11- fluoro- N, 7- dimethyl -4- oxo -4,5,6,7,13,14- hexahydro -1,15- ethylene bridge pyrazolos Azacyclotridecane -13- the formamides (61) of [4,3-f] [1,4,8,10] benzo oxa- three

Step 1. is by 61-1 hydrochloride (250.42mg, 1.13mmol) and 5- chlorine pyrazolo [1,5-a] pyrimidine -3- formic acid Ethyl ester (254.96mg, 1.13mmol) combination and addition in the ethanol (5.65mL) permitted Buddhist nun Xi Shi alkali (1.46g, 11.30mmol, 1.97mL).Stirring mixture and it is warming up to 80 DEG C.Reaction is examined after 3 hours and confirms that reaction is complete by LC-MS.Cooling is anti- Answer thing and handled with water and ethyl acetate.Water layer is extracted with ethyl acetate again twice.With the organic layer of salt water washing ECDC simultaneously, warp Sodium sulphate is dried, filtering.Thick material is purified by column chromatography (DCM/ methanol), obtains 61-2 (176mg).Pass through acidifying water Layer obtains 61-2 (130mg) and is extracted with ethyl acetate and purifies again, obtains final 72% yield.

Step 2. is by 61-2 (130.00mg, 347.30 μm of ol) and (R)-(2- hydroxypropyls) t-butyl carbamate (182.56mg, 1.04mmol) combination and azeotropic drying under reduced pressure in toluene.Gained is dissolved in two through drying compound In chloromethanes (231.53 μ L) and triphenylphosphine (277.83mg, 1.06mmol) is added in solution at room temperature.About 10 points Zhong Hou, mixture and addition DIAD (214.19mg, 1.06mmol, 207.95 μ L) are cooled down in ice bath.Gradual reaction stirred To room temperature and stir 19 hours, be quenched by being added in water (4 times of solvent volumes) and extracted with DCM (3 × 3mL).Use Na₂SO₄ Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (ISCO systems, silica gel (12g), 0-100% acetic acid second The hexane solution of ester), obtain 61-3 (138.5mg, 57% yield).

Step 3. is to 61-3 (138.50mg, 201.09 μm of ol) in methanol (0.5mL), THF (2.00mL) and water LiOH (2.0M, 0.15mL) is added in solution in (1.80mL).It is complete until hydrolyzing that mixture is stirred at room temperature.Use HCl Reactant is neutralized to pH about 5 and extracted with DCM.Use Na₂SO₄The extract through merging is dried, filtering, is concentrated and in high vacuum Middle drying, obtain 61-4 (100mg).

Step 4. is added into solution of the 61-4 (53.5mg, 0.10mmol) in DCM (4.5mL) and DMF (0.5mL) FDPP (50.3mg, 0.13mmol), permitted Buddhist nun Xi Shi alkali (130.1mg, 1.01mmol) and methylamine hydrochloride (13.6mg, 0.20mmol).Mixture is stirred untill LC-MS displayings are completed, then uses Na₂CO₃The aqueous solution is quenched.With DCM (3 × Mixture 50mL) is extracted, uses Na₂SO₄Dry the extract through merging and concentrate under reduced pressure.Flash chromatography (ISCO systems, Silica gel (40g), the dichloromethane solution of 0-8.75% methanol) 61-5 (24.4mg, 44% yield) is provided.

The reactions steps 4 that 61-5 is followed in universal method H are converted into 61.

Compound 27 to 31 uses A-5 and Loprazolam (S) -1- ((tert-butoxy carbonyls according to universal method F in step 1 Base) amino) butyl- 2- base esters (be used for 27), Loprazolam (S) -1- ((tert-butoxycarbonyl) amino) propyl- 2- base esters (be used for 28), Loprazolam (R) -1- ((tert-butoxycarbonyl) amino) propyl- 2- base esters (being used for 29), Loprazolam (R) -2- ((tertiary fourths Epoxide carbonyl) amino) propyl diester (be used for 30) and Loprazolam (S) -2- ((tert-butoxycarbonyl) amino) propyl ester (being used for 31) Prepare.

Compound 32 uses A-6 and Loprazolam (R) -1- ((tert-butoxycarbonyl) according to universal method F in step 1 Amino) preparation of propyl- 2- base esters.

Compound 34 and 35 is prepared according to universal method A and F, wherein using 3- ethyoxyl -2- methyl in universal method A Ethyl acrylate obtains the chloro- 6- methylpyrazoles of 5-, and simultaneously [1,5-a] pyrimidine -3- Ethyl formates rather than 5- chlorine pyrazolo [1,5-a] are phonetic Pyridine -3- Ethyl formates (A-1-8), and (2- chloroethyls) t-butyl carbamate (being used for 34) and first are used in universal method F Alkyl sulfonic acid (R) -1- ((tert-butoxycarbonyl) amino) propyl- 2- base esters (are used for 35).

Compound 36 and 37 is prepared according to universal method A and F, wherein in universal method A using A-1-8 (be used for 36) and The chloro- 6- methylpyrazoles of 5- simultaneously [1,5-a] pyrimidine -3- Ethyl formates (37), and the fluoro- 2- hydroxyls of 5- are substituted using Benzaldehyde,2-hydroxy Benzaldehyde, and (2- chloroethyls) t-butyl carbamate (being used for 36 and 37) is used in universal method F.

Compound 39 is prepared according to universal method A and F, wherein using 5- amino -3- ethyl -1H- pyrroles in universal method A Azoles -4- Ethyl formates substitute 5- amino -1H- pyrazoles -4- Ethyl formates (A-1-6), and Loprazolam is used in universal method F (R) -1- ((tert-butoxycarbonyl) amino) propyl- 2- base esters.

Compound 40 substitutes 33-3 using 40-5 according to universal method I and prepared.

Compound 42 to 54 substitutes (1S, 2S) -2- in universal method L according to universal method L using following initial substance It is prepared by amino cyclopentyl -1- alcohol.

Compound 55 to 57 is prepared according to universal method E, wherein using the alternative compounds 6 of compound 7, and use dimethylamine (being used for 55), methylamine (being used for 56) and pyrrolidines (57).

Compound 59 and 60 according to universal method M use (R)-(2- hydroxypropyls) t-butyl carbamate substitute (S)- It is prepared by (2- hydroxybutyls) t-butyl carbamate.

Compound 62 substitutes methylamine using dimethylamine according to universal method N and prepared.

Bioanalysis

Carry out CD74-ROS1 and EML4-ALK Ba/F3 stable cell lines and analysis of cell proliferation.

CD74-ROS1 wild type genes and EML4-ALK wild type genes (variant 1) are synthesized in GenScript and choosing is grown In pCDH-CMV-MCS-EF1-Puro plastids (System Biosciences companies).Ba/F3-CD74-ROS1 and Ba/F3- EML4-ALK wild-type cells system is by using the slow-virus infection Ba/ containing CD74-ROS1 wild types and EML4-ALK wild types F3 cells produce.Handled by puromycin, then remove IL-3 selection stable cell lines.3000 cells are inoculated in 384 It is overnight in the white disk of hole, then carry out compound processing.After the compound incubation 72 hours of various concentration, use ATP detection and analysis (Promega) of the CellTiter-Glo based on luciferase follow the scheme measurement cell propagation of manufacturer. IC is performed using GraphPad Prism softwares (GraphPad companies, Santiago, California)₅₀Value measure.

Analysis of cell proliferation

Colorectum is cultivated in being supplemented with the DMEM culture mediums of 10% hyclone and 100U/mL penicillin/streptomycins Cell line KM 12 (containing endogenous TPM3-TRKA fusions) cell.5000 cells are inoculated in 384 hole white disks and tieed up Hold 24 hours, then carry out compound processing.After cultivating 72 hours, ATPs of the CellTiter-Glo based on luciferase is used Detection and analysis (Promega) follow the scheme measurement cell propagation of manufacturer.Use GraphPad Prism softwares (GraphPad Company, Santiago, California) perform IC₅₀Value measure.Or primary thrombocytosis cell line SET-2 cells (are contained Have endogenous JAK2V618F point mutation) or t cell lymphoma Karpas-299 cell lines (containing endogenous NPM-ALK fusions) Cultivated in being supplemented with the RPMI culture mediums of 10% hyclone and 100U/mL penicillin/streptomycins.5000 cells are inoculated with Maintained 24 hours in 384 hole white disks, then carry out compound processing.After cultivating 72 hours, CellTiter-Glo is used ATP detection and analysis (Promega) based on luciferase follow the scheme measurement cell propagation of manufacturer.Use GraphPad Prism softwares (GraphPad companies, Santiago, California) perform IC₅₀Value measure.

Claims

1. a kind of compound of formula I,

Wherein

M is CR^4aOr N；

M¹For CR⁵Or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹For H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen atom in aryl is optionally Independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl )₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkane Base) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆ Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkane Base) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH (C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O) NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH(C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆ Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

Each R²And R³It independently is H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O)OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀It is each in aryl Hydrogen atom is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁- C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O)(C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkane Base ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N (C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；Or R² And R³C is optionally formed together with the carbon atom connected with it₅-C₇Cycloalkyl or 5 yuan are to 7 circle heterocycles alkyl；Or R²And R⁶With it The atom connected is optionally formed 5 yuan to 7 circle heterocycles alkyl together；

R⁴、R^4aAnd R⁵Respectively it independently is H, fluorine, chlorine, bromine, C₁-C₆Alkyl ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl)₂Or-CF₃；

R⁶For H, C₁-C₆Alkyl or 3 yuan are to 7 circle heterocycles alkyl, wherein C₁-C₆Alkyl or 3 yuan are former to each hydrogen in 7 circle heterocycles alkyl Son is optionally independently through following substitution：Halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆ Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、C₃-C₆ Cycloalkyl or it is monocyclic 5 yuan to 7 circle heterocycles alkyl；

Each R⁷And R⁸It independently is H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 3 yuan to 7 circle heterocycles alkane Base, C₆-C₁₀Aryl or heteroaryl；

Each R⁹It independently is H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 3 yuan to 7 circle heterocycles alkyl, C₆-C₁₀Aryl or monocyclic or bicyclic heteroaryl；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 3 yuan to 7 Circle heterocycles alkyl, C₆-C₁₀Each hydrogen atom in aryl or monocyclic or bicyclic heteroaryl is optionally independently through following substitution：Deuterium, Halogen, C₁-C₆Alkyl, C₁-C₆Alkylhalide group or-OR⁷；

Each Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶Or Z⁷It independently is N, NH or C (R¹⁰), wherein each R¹⁰It independently is H, deuterium, halogen, C₁-C₆Alkane Base ,-OC₁-C₆Alkyl ,-OH ,-NH₂、-NH(C₁-C₆Alkyl) ,-NH (phenyl) ,-NH (heteroaryl) ,-CN or-CF₃,

N is 1 or 2；And

On condition that Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶Or Z⁷At least one of be N or NH；And on condition that at least one R¹、R²Or R³It is not H；

Or its pharmaceutically acceptable salt.

2. compound according to claim 1, it has Formulas I a

Wherein

M is CR^4aOr N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹For C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷Or-C (O) NR⁷R⁸； Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen atom in aryl is optionally independently Through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC (O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkane Base) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,- NHS(O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,- NHS(O)NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆ Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkane Base) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkane Base)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆ Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆ Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、- P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

R²And R³Respectively it independently is H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O)OR⁷Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀It is each in aryl Hydrogen atom is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁- C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O)(C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkane Base ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N (C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

Each Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶Or Z⁷It independently is N, NH or C (R¹⁰), wherein each R¹⁰It independently is H, deuterium, halogen, C₁-C₆Alkane Base ,-OC₁-C₆Alkyl ,-OH ,-NH₂、-NH(C₁-C₆Alkyl) ,-NH (phenyl) ,-NH (heteroaryl) ,-CN or-CF₃, and

Or its pharmaceutically acceptable salt.

3. compound according to claim 1 or 2 or its pharmaceutically acceptable salt, wherein Z¹、Z⁴And Z⁷For N and Z²、Z³、 Z⁵And Z⁶For CH.

4. compound according to any one of the preceding claims or its pharmaceutically acceptable salt, wherein X¹For N (R⁹)。

5. compound according to any one of the preceding claims or its pharmaceutically acceptable salt, wherein R⁹For H。

6. compound according to any one of the preceding claims or its pharmaceutically acceptable salt, wherein X²For O。

7. compound according to any one of the preceding claims or its pharmaceutically acceptable salt, wherein R²For C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷Or-C (O) NR⁷R⁸；Wherein C₁- C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen atom in aryl is optionally independently through following Substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆ Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl, NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl, N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkane Base)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂ (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,- NHS(O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,- C(O)N(C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,- S(O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁- C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl, and R³For H.

8. compound or its pharmaceutically acceptable salt according to any claim in claim 1 to 6, wherein R²For H, and R³For C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷Or-C (O) NR⁷R⁸； Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen atom in aryl is optionally independently Through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC (O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl, N (C₁-C₆Alkane Base) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,- NHS(O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,- NHS(O)NH₂、NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkane Base) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkane Base) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkane Base)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆ Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆ Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、- P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl.

9. compound or its pharmaceutically acceptable salt according to any claim in claim 1 to 6, wherein R²And R³For H.

10. the compound according to any claim in claim 1 to 7, it has Formula II

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹And R²Respectively it independently is C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷ Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen in aryl is former Son is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁- C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkane Base ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁- C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂ (C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、- NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkane Base)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S(O)N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆ Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkane Base)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、-C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

R⁴And R⁵Respectively it independently is H, fluorine, chlorine, bromine, C₁-C₆Alkyl ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NHC₁-C₆Alkyl ,-N (C₁- C₆Alkyl)₂Or-CF₃；

Each R⁷And R⁸It independently is H, deuterium, C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 3 yuan to 7 circle heterocycles alkane Base, C₆-C₁₀Aryl or heteroaryl；And

Or its pharmaceutically acceptable salt.

11. the compound according to any claim in claim 1 to 7, it has formula III

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹And R²Respectively it independently is C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷ Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen in aryl is former Son is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁- C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkane Base, N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆ Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁- C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆ Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O) NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O) NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH(C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆ Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

Or its pharmaceutically acceptable salt.

12. according to the compound described in any claim in claim 1 to 6 or 8, it has formula IV

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹And R³Respectively it independently is C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷ Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen in aryl is former Son is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁- C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkane Base, N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆ Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁- C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆ Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O) NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O) NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH(C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆ Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

Or its pharmaceutically acceptable salt.

13. according to the compound described in any claim in claim 1 to 6 or 8, it has Formula V

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

R¹And R³Respectively it independently is C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, C₆-C₁₀Aryl ,-C (O) OR⁷ Or-C (O) NR⁷R⁸；Wherein C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl and C₆-C₁₀Each hydrogen in aryl is former Son is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁- C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkane Base ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁- C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂ (C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、- NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkane Base)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S(O)N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆ Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkane Base)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl；

Or its pharmaceutically acceptable salt.

14. according to the compound described in any claim in claim 1 to 6 or 9, it has Formula IV

Wherein

M is CH or N；

X¹And X²It independently is S, S (O), S (O)₂, O or N (R⁹)；

Or its pharmaceutically acceptable salt.

15. compound according to any one of the preceding claims or its pharmaceutically acceptable salt, wherein R⁵ For-H.

16. compound according to any one of the preceding claims or its pharmaceutically acceptable salt, wherein R⁴ For-F.

17. compound according to any claim in claim 1 to 7,10,11,15 or 16 or its can pharmaceutically connect The salt received, wherein R²In the presence of be C₁-C₆Alkyl and C₁-C₆Each hydrogen atom in alkyl is optionally independently through following substitution：Deuterium, Halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N (C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、- NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkane Base) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS (O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁- C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkane Base) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkane Base)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl.

18. compound according to any claim in claim 1 to 7,10,11 or 15 to 17 or its can pharmaceutically connect The salt received, wherein R²In the presence of be C₁-C₆Alkyl, it is through selected from the substitution of one or more parts of the group consisted of：-F、- OH、-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) and-N (C₁-C₆Alkyl)₂。

19. compound according to any claim in claim 1 to 7,10,11 or 15 to 18 or its can pharmaceutically connect The salt received, wherein R²In the presence of be methyl.

20. compound according to any claim in claim 1 to 7,10,11 or 15 to 18 or its can pharmaceutically connect The salt received, wherein R²In the presence of be ethyl.

21. compound according to any claim in claim 1 to 7,10,11 or 15 to 18 or its can pharmaceutically connect The salt received, wherein R²In the presence of be hydroxymethyl.

22. compound according to any claim in claim 1 to 7,10,11 or 15 to 18 or its can pharmaceutically connect The salt received, wherein R²In the presence of be methyl fluoride.

23. compound according to any claim in claim 1 to 7,10,11 or 15 to 18 or its can pharmaceutically connect The salt received, wherein R²In the presence of be methoxy.

24. compound according to any claim in claim 1 to 7,10,11 or 15 to 18 or its can pharmaceutically connect The salt received, wherein R²In the presence of be difluoromethyl.

25. compound according to any claim in claim 1 to 7,10,11 or 15 to 18 or its can pharmaceutically connect The salt received, wherein R²In the presence of be trifluoromethyl.

26. compound according to any claim in claim 1 to 7,10,11 or 15 to 18 or its can pharmaceutically connect The salt received, wherein R²In the presence of be C₁-C₆Alkyl, its warp-NH₂、-NH(C₁-C₆Alkyl) or-N (C₁-C₆Alkyl)₂Substitution.

27. compound according to any claim in claim 1 to 7,10,11 or 15 to 18 or its can pharmaceutically connect The salt received, wherein R²In the presence of be methyl, its warp-NH₂、-NH(C₁-C₆Alkyl) or-N (C₁-C₆Alkyl)₂Substitution.

28. compound according to any claim in claim 1 to 7,10,11 or 15 to 18 or its can pharmaceutically connect The salt received, wherein R²In the presence of be methyl, its warp-N (CH₃)₂Substitution.

29. compound according to any claim in claim 1 to 7,10,11,15 or 16 or its can pharmaceutically connect The salt received, wherein R²In the presence of be-C (O) NR⁷R⁸。

30. compound according to claim 29 or its pharmaceutically acceptable salt, wherein R⁷And R⁸For H.

31. compound according to any claim in claim 1 to 6,8,12,13,15 or 16 or its pharmaceutically may be used The salt of receiving, wherein R³In the presence of be C₁-C₆Alkyl and C₁-C₆Each hydrogen atom in alkyl is optionally independently through following substitution： Deuterium, halogen ,-OH ,-CN ,-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkane Base ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkane Base)₂、-NHC(O)OC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂ (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,- NHS(O)₂NH(C₁-C₆Alkyl) ,-NHS (O) N (C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N (C₁-C₆Alkyl) S (O)₂N(C₁-C₆Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,- C(O)N(C₁-C₆Alkyl)₂、-SC₁-C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,- S(O)₂NH(C₁-C₆Alkyl) ,-S (O) N (C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁- C₆Alkyl)₂、C₃-C₆Cycloalkyl or 3 yuan are to 7 circle heterocycles alkyl.

32. compound according to any claim in claim 1 to 6,8,12,13,15,16 or 31 or its pharmaceutically Acceptable salt, wherein R³In the presence of be C₁-C₆Alkyl, it selected from one or more parts of the group consisted of through taking Generation：-F、-OH、-OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) and-N (C₁-C₆Alkyl)₂。

33. compound or its medicine according to any claim in claim 1 to 6,8,12,13,15,16,31 or 32 Acceptable salt, wherein R on³In the presence of be methyl.

34. compound or its medicine according to any claim in claim 1 to 6,8,12,13,15,16,31 or 32 Acceptable salt, wherein R on³In the presence of be ethyl.

35. compound or its medicine according to any claim in claim 1 to 6,8,12,13,15,16,31 or 32 Acceptable salt, wherein R on³In the presence of be hydroxymethyl.

36. compound or its medicine according to any claim in claim 1 to 6,8,12,13,15,16,31 or 32 Acceptable salt, wherein R on³In the presence of be methyl fluoride.

37. compound or its medicine according to any claim in claim 1 to 6,8,12,13,15,16,31 or 32 Acceptable salt, wherein R on³In the presence of be methoxy.

38. compound or its medicine according to any claim in claim 1 to 6,8,12,13,15,16,31 or 32 Acceptable salt, wherein R on³In the presence of be difluoromethyl.

39. compound or its medicine according to any claim in claim 1 to 6,8,12,13,15,16,31 or 32 Acceptable salt, wherein R on³In the presence of be trifluoromethyl.

40. compound or its medicine according to any claim in claim 1 to 6,8,12,13,15,16,31 or 32 Acceptable salt, wherein R on³In the presence of be C₁-C₆Alkyl, its warp-NH₂、-NH(C₁-C₆Alkyl) or-N (C₁-C₆Alkyl)₂Take Generation.

41. compound or its medicine according to any claim in claim 1 to 6,8,12,13,15,16,31 or 32 Acceptable salt, wherein R on³In the presence of be methyl, its warp-NH₂、-NH(C₁-C₆Alkyl) or-N (C₁-C₆Alkyl)₂Substitution.

42. compound or its medicine according to any claim in claim 1 to 6,8,12,13,15,16,31 or 32 Acceptable salt, wherein R on³In the presence of be methyl, its warp-N (CH₃)₂Substitution.

43. compound according to any claim in claim 1 to 6,8,12,13,15 or 16 or its pharmaceutically may be used The salt of receiving, wherein R³In the presence of be-C (O) NR⁷R⁸。

44. compound according to claim 43 or its pharmaceutically acceptable salt, wherein R⁷And R⁸For H.

45. compound according to any one of the preceding claims or its pharmaceutically acceptable salt, wherein R¹Deposit When be C₁-C₆Alkyl and C₁-C₆Each hydrogen atom in alkyl is optionally independently through following substitution：Deuterium, halogen ,-OH ,-CN ,- OC₁-C₆Alkyl ,-NH₂、-NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂、-NHC(O)C₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) C₁-C₆Alkyl ,-NHC (O) NH₂、-NHC(O)NHC₁-C₆Alkyl ,-N (C₁-C₆Alkyl) C (O) NH₂、-N(C₁-C₆Alkyl) C (O) NHC₁-C₆Alkyl ,-NHC (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) C (O) N (C₁-C₆Alkyl)₂、-NHC(O)OC₁-C₆Alkane Base ,-N (C₁-C₆Alkyl) C (O) OC₁-C₆Alkyl ,-NHS (O) (C₁-C₆Alkyl) ,-NHS (O)₂(C₁-C₆Alkyl) ,-N (C₁-C₆Alkane Base) S (O) (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O)₂(C₁-C₆Alkyl) ,-NHS (O) NH₂、-NHS(O)₂NH₂、-N(C₁-C₆ Alkyl) S (O) NH₂、-N(C₁-C₆Alkyl) S (O)₂NH₂、-NHS(O)NH(C₁-C₆Alkyl) ,-NHS (O)₂NH(C₁-C₆Alkyl) ,- NHS(O)N(C₁-C₆Alkyl)₂、-NHS(O)₂N(C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O) NH (C₁-C₆Alkyl) ,-N (C₁-C₆ Alkyl) S (O)₂NH(C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl) S (O) N (C₁-C₆Alkyl)₂、-N(C₁-C₆Alkyl) S (O)₂N(C₁-C₆ Alkyl)₂、-CO₂H、-C(O)OC₁-C₆Alkyl ,-C (O) NH₂、-C(O)NH(C₁-C₆Alkyl) ,-C (O) N (C₁-C₆Alkyl)₂、-SC₁- C₆Alkyl ,-S (O) C₁-C₆Alkyl ,-S (O)₂C₁-C₆Alkyl ,-S (O) NH (C₁-C₆Alkyl) ,-S (O)₂NH(C₁-C₆Alkyl) ,-S (O)N(C₁-C₆Alkyl)₂、-S(O)₂N(C₁-C₆Alkyl)₂、-P(C₁-C₆Alkyl)₂、-P(O)(C₁-C₆Alkyl)₂、C₃-C₆Cycloalkyl Or 3 yuan to 7 circle heterocycles alkyl.

46. compound according to any one of the preceding claims or its pharmaceutically acceptable salt, wherein R¹Deposit When be C₁-C₆Alkyl, it substitutes through one or more-F or-OH.

47. compound or its pharmaceutically acceptable salt according to any claim in claim 1 to 46, wherein R¹ In the presence of be C₁-C₆Alkyl.

48. compound or its pharmaceutically acceptable salt according to any claim in claim 1 to 46, wherein R¹ In the presence of be methyl.

49. compound or its pharmaceutically acceptable salt according to any claim in claim 1 to 46, wherein R¹ In the presence of be ethyl.

50. compound or its pharmaceutically acceptable salt according to any claim in claim 1 to 46, wherein R¹ In the presence of be 2- hydroxy-ethyls.

51. compound or its pharmaceutically acceptable salt according to any claim in claim 1 to 46, wherein R¹ In the presence of be the fluoro- ethyls of 2-.

52. compound or its pharmaceutically acceptable salt according to any claim in claim 1 to 46, wherein R¹ In the presence of be 2- hydroxyl -2- propyl group.

53. compound according to any one of the preceding claims or its pharmaceutically acceptable salt, wherein M are deposited When be CR^4a。

54. compound according to any one of the preceding claims or its pharmaceutically acceptable salt, wherein when In the presence of, M CR^4a, and R^4aFor H.

55. compound according to claim 1, it has the formula selected from the group consisted of：

And

Or its pharmaceutically acceptable salt.

56. compound according to claim 1, it has the formula selected from the group consisted of：

And

Or its pharmaceutically acceptable salt.

57. compound according to claim 1, it has the formula selected from the group consisted of：

And

Or its pharmaceutically acceptable salt.

58. compound according to claim 1, it has the formula selected from the group consisted of：

And

Or its pharmaceutically acceptable salt.

59. compound according to claim 1, it has the formula selected from the group consisted of：

And

Or its pharmaceutically acceptable salt.

60. compound according to claim 1, it has the formula selected from the group consisted of：

And

Or its pharmaceutically acceptable salt.

61. a kind of medical composition, it include according to the compound of any claim in preceding claims or its pharmaceutically Acceptable salt, and optionally at least a kind of diluent, carrier or excipient.

62. a kind for the treatment of cancer, pain, sacred disease, the method for autoimmune disease or inflammation, it, which includes administration, needs this to control At least one compound according to any claim in claim 1 to 60 of the individual effective dose for the treatment of or its pharmaceutically Acceptable salt.

63. a kind of compound according to any claim in claim 1 to 60 or its pharmaceutically acceptable salt Purposes, it is used for the medicine for preparing treating cancer, pain, sacred disease, autoimmune disease or inflammation.

64. a kind of compound according to any claim in claim 1 to 60 or its pharmaceutically acceptable salt Purposes, it is used for treating cancer, pain, sacred disease, autoimmune disease or inflammation.

A kind of 65. protein or EGFR-TK for suppressing to include one or more of MET, ALK, ROS1, AXL, TRK and JAK Method, it includes making at least one of the cell for including one or more this kind of kinases and effective dose according to claim 1 to 60 The compound of middle any claim or its pharmaceutically acceptable salt and/or connect with least one medical composition of the invention Touch, wherein the contact in vitro, it is in vitro or in vivo carry out.

66. a kind of compound according to any claim in claim 1 to 60, it is used for the cancer for treating patient.

67. a kind of compound according to any claim in claim 1 to 60, it is used for the inflammation for treating patient.